Device, system, and method for targeted delivery of anti-inflammatory medicaments to a mammalian subject

ABSTRACT

A device, a system, or a method is described for treating a disease or condition of one or more joints of articulating bone in a mammalian subject. A device is described which includes one or more substrates configured to contact one or more body contours at one or more joints of articulating bone of a mammalian subject; and an applicator supported by the one or more substrates and configured to inject one or more medicaments to one or more joint tissues of the mammalian subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is related to and claims the benefit of theearliest available effective filing date(s) from the following listedapplication(s) (the “Related applications”) (e.g., claims earliestavailable priority dates for other than provisional patent applicationsor claims benefits under 35 USC §119(e) for provisional patentapplications, for any and all parent, grandparent, great-grandparent,etc. applications of the Related application(s)). All subject matter ofthe Related applications and of any and all parent, grandparent,great-grandparent, etc. applications of the Related applications isincorporated herein by reference to the extent such subject matter isnot inconsistent herewith.

RELATED APPLICATIONS

-   -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. to be assigned, Docket No.        0605-004-009-000000, entitled DEVICE, SYSTEM, AND METHOD FOR        TARGETED DELIVERY OF ANTI-INFLAMMATORY MEDICAMENTS TO A        MAMMALIAN SUBJECT, naming Philip A. Eckhoff, Roderick A. Hyde,        Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Dennis J.        Rivet, Elizabeth A. Sweeney, Lowell L. Wood, Jr. and        Victoria Y. H. Wood as inventors, filed 13 Nov. 2009, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. to be assigned, Docket No.        0605-004-010-000000, entitled DEVICE, SYSTEM, AND METHOD FOR        TARGETED DELIVERY OF ANTI-INFLAMMATORY MEDICAMENTS TO A        MAMMALIAN SUBJECT, naming Philip A. Eckhoff, Roderick A. Hyde,        Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Dennis J.        Rivet, Elizabeth A. Sweeney, Lowell L. Wood, Jr. and        Victoria Y. H. Wood as inventors, filed 13 Nov. 2009, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. to be assigned, Docket No.        0605-004-11-000000, entitled DEVICE, SYSTEM, AND METHOD FOR        TARGETED DELIVERY OF ANTI-INFLAMMATORY MEDICAMENTS TO A        MAMMALIAN SUBJECT, naming Philip A. Eckhoff, Roderick A. Hyde,        Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Dennis J.        Rivet, Elizabeth A. Sweeney, Lowell L. Wood, Jr. and        Victoria Y. H. Wood as inventors, filed 13 Nov. 2009, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. to be assigned, Docket No.        0605-004-12-000000, entitled DEVICE, SYSTEM, AND METHOD FOR        TARGETED DELIVERY OF ANTI-INFLAMMATORY MEDICAMENTS TO A        MAMMALIAN SUBJECT, naming Philip A. Eckhoff, Roderick A. Hyde,        Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Dennis J.        Rivet, Elizabeth A. Sweeney, Lowell L. Wood, Jr. and        Victoria Y. H. Wood as inventors, filed 13 Nov. 2009, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.

The United States Patent Office (USPTO) has published a notice to theeffect that the USPTO's computer programs require that patent applicantsreference both a serial number and indicate whether an application is acontinuation or continuation-in-part. Stephen G. Kunin, Benefit ofPrior-Filed application, USPTO Official Gazette Mar. 18, 2003, availableat http://www.uspto.gov/web/offices/com/sol/og/2003/week11/patbene.htm.The present Applicant Entity (hereinafter “Applicant”) has providedabove a specific reference to the application(s) from which priority isbeing claimed as recited by statute. Applicant understands that thestatute is unambiguous in its specific reference language and does notrequire either a serial number or any characterization, such as“continuation” or “continuation-in-part,” for claiming priority to U.S.patent applications. Notwithstanding the foregoing, Applicantunderstands that the USPTO's computer programs have certain data entryrequirements, and hence Applicant is designating the present applicationas a continuation-in-part of its parent applications as set forth above,but expressly points out that such designations are not to be construedin any way as any type of commentary and/or admission as to whether ornot the present application contains any new matter in addition to thematter of its parent application(s).

SUMMARY

A device is described for treating a disease or a condition of one ormore joints of articulating bone in a mammalian subject. The deviceprovides one or more medicaments to one or more joints of the mammaliansubject. A device is described herein that includes one or more sheathsconfigured to contact one or more body contours in proximity to one ormore joints of articulating bone of a mammalian subject; and one or moremicrojet applicators supported by the one or more sheaths and configuredto inject one or more medicaments to one or more joint tissues of themammalian subject. The one or more applicators can include one or morehigh speed microjets, e.g., nanoliter-volume pulsed microjets. The oneor more sheaths can include a sleeve-shaped article of clothing or asleeve-shaped body covering. In an aspect, the one or more sheaths caninclude shirt sleeve, pant, leg covering, glove, stocking, bandage-likecovering, brace, knee brace, elbow brace, ankle brace, foot brace, handbrace, or spinal brace. The one or more joint tissues can include one ormore of a fibrous capsule, subsynovium, synovial membrane, synovium,joint cavity, synovial fluid, articular cartilage, subchondral bone, orligament. The one or more joints can include a synovial joint,cartilaginous joint, or fibrous joint. In an aspect, the one or moreapplicators supported by the one or more sheaths can be configured torespond to one or more sensors, wherein the one or more applicators areconfigured to inject the one or more medicaments to the one or morejoint tissues of the mammalian subject.

In an aspect, the device can further include one or more sensorsconfigured to detect movement of the one or more body contours. The oneor more sensors can be configured to monitor joint movement, bodymovement, or gait of the mammalian subject. The one or more sensors canbe configured to monitor posture of the mammalian subject. The one ormore sensors can be configured to monitor frequency of joint use orlevel of effort used by the one or more joints. In a detailed aspect,the level of effort used by the one or more joints includes measuredeffort or inferred effort. The one or more sensors can be configured tomonitor a preselected set of activity profiles.

In an aspect, the device can further include one or more sensorsconfigured to detect one or more physiological conditions of themammalian subject. The one or more sensors can be configured to detecttissue swelling, tissue pressure, tissue color, tissue temperature,environmental temperature, electrical property of tissue, opticalproperty of tissue, perspiration, or presence of an analyte. The analytecan include an inflammatory marker, antibody, or cytokine.

In an aspect, the device can further include one or more sensorsconfigured to determine quality of location or quality of contactplacement of the one or more sheaths on the one or more body contours.

In an aspect, the device can further include a controller configured tocontrol release of the one or more medicaments from the one or moreapplicators. The controller can be configured to control a timed-releasedosage of the one or more medicaments. The controller can be configuredto report quantity and frequency of dosage of the one or moremedicaments. The controller can be configured to control a maximumdosage of the one or more medicaments for a time period. The controllercan be configured to activate the one or more applicators based at leastin part on an activity history of the mammalian subject. In a detailedaspect, the activity history can include joint movement or gait of themammalian subject. The activity history can include, but is not limitedto, frequency of use of the one or more joints, measured effort level ofthe one or more joints, inferred effort level of the one or more joints,or a preselected activity profile. The device can further include one ormore sensors, wherein the controller is configured to respond to the oneor more sensors. The one or more sensors can be configured to detect oneor more conditions at one or more of the one or more joints and thecontroller is configured to control release of the one or moremedicaments at others of the one or more joints of the mammaliansubject.

The device can further include a power source. The power source caninclude, but is not limited to, a motion-activated generator, solarcell, fuel cell, wireless source, battery or microbattery. The powersource can be powered by motion of the body of the mammalian subject.

The one or more applicators can further include, but are not limited to,tissue permeabilization components including one or more of electronics,ultrasonics, chemical permeation enhancer, iontophoresis, microdialysis,ultrafiltration, electromagnetic, electroosmosis, sonophoresis,microdialysis, suction, electroporation, thermal poration,microporation, heating component, or laser. The chemical permeationenhancer can include, but is not limited to, a dermal penetrationenhancer including one or more esters including long chain alkylpara-aminobenzoate, long chain alkyl dimethyl-para-aminobenzoate, longchain alkyl cinnamate, long chain alkyl methoxycinnamate, long chainalkyl salicylate, octyl dimethyl-para-aminobenzoate, octylpara-methoxycinnamate, or octyl salicylate.

The one or more sheaths can include a tourniquet configured to applyintermittent pressure in the region of the jointed area. The tourniquetcan be configured to apply a constricting force thereby causing the oneor more applicators to penetrate the stratum corneum of the skin of themammalian subject.

The device can further include a component for transientmechanical/electrical acceleration of the one or more medicaments fromthe high speed microjets. The component for transientmechanical/electrical acceleration can include a fluid displacementactuator configured as one or more piezoelectric actuators, one or moresprings, one or more solenoids, one or more magnets, one or more motors,or one or more compressed gas actuators. The component formechanical/electrical acceleration is configured to apply concentrationgradients of the one or more medicaments in a time-dependent manner.

The one or more medicaments can include, but are not limited to,steroids, corticosteroids, analgesics, COX-2 inhibitors, or NSAIDs. TheNSAID include, but is not limited to, acemetacin, amtolmetin,azapropazone, benorilate, benoxaprofen, benzydamine hydrochloride,bromfenal, bufexamac, butibufen, carprofen, celecoxib, cholinesalicylate, diclofenac dipyone, droxicam, etodolac, etofenamate,etoricoxib, felbinac, fentiazac, floctafenine, ibuprofen, indoprofen,isoxicam, lomoxicam, loxoprofen, licofelone, fepradinol, magnesiumsalicylate, meclofenamic acid, meloxicam, morniflumate, niflumic acid,nimesulide, oxaprozen, piketoprofen, priazolac, pirprofen,propyphenazone, proquazone, rofecoxib, salalate, sodium salicylate,sodium thiosalicylate, suprofen, tenidap, tiaprofenic acid, trolaminesalicylate, zomepirac, aclofenac, aloxiprin, naproxen, aproxen, aspirin,diflunisal, fenoprofen, indomethacin, mefenamic acid, piroxicam,phenylbutazone, salicylamide, salicylic acid, sulindac, desoxysulindac,tenoxicam, tramadol, ketoralac, clonixin, fenbufen, benzydaminehydrochloride, meclofenamic acid, flufenamic acid, or tolmetin. Thedevice can further include a pharmaceutical composition including theone or more medicaments in a thixotropic medium. The device can furtherinclude, but is not limited to, one or more microneedles, one or moremicrofine lances, one or more microfine cannulas, one or moremicroprojections, or one or more electrodes, supported by the one ormore sheaths and configured to inject the one or more medicaments to theone or more joint tissues of the mammalian subject. The one or moreapplicators can be configured to apply the one or more medicaments in atime-dependent manner. The one or more applicators can be configured toapply the one or more medicaments in concentration gradients in thetime-dependent manner. The one or more medicaments can be configured tohave a short effective half-life. The one or more medicaments can beconfigured to have a long effective half-life.

A method is described herein that includes injecting one or moremedicaments to one or more joint tissues of a mammalian subject, whereinthe injecting of the one or more medicaments is via a device includingone or more sheaths configured to contact one or more body contours inproximity to one or more joints of articulating bone of the mammaliansubject; and one or more microjet applicators supported by the one ormore sheaths and configured to inject one or more medicaments to one ormore joint tissues of the mammalian subject.

The one or more applicators can include one or more high speedmicrojets, e.g., nanoliter-volume pulsed microjets. The one or moresheaths can include a sleeve-shaped article of clothing or asleeve-shaped body covering. In an aspect, the one or more sheaths caninclude shirt sleeve, pant, leg covering, glove, stocking, bandage-likecovering, brace, knee brace, elbow brace, ankle brace, foot brace, handbrace, or spinal brace. The one or more joint tissues can include one ormore of a fibrous capsule, subsynovium, synovial membrane, synovium,joint cavity, synovial fluid, articular cartilage, subchondral bone, orligament. The one or more joints can include a synovial joint,cartilaginous joint, or fibrous joint. In an aspect, the one or moreapplicators supported by the one or more sheaths can be configured torespond to one or more sensors, wherein the one or more applicators areconfigured to inject the one or more medicaments to the one or morejoint tissues of the mammalian subject.

In an aspect, the method can further include providing one or moresensors configured to detect movement of the one or more body contours.The one or more sensors can be configured to monitor joint movement,body movement, or gait of the mammalian subject. The one or more sensorscan be configured to monitor posture of the mammalian subject. The oneor more sensors can be configured to monitor frequency of joint use orlevel of effort used by the one or more joints. In a detailed aspect,the level of effort used by the one or more joints includes measuredeffort or inferred effort. The one or more sensors can be configured tomonitor a preselected set of activity profiles.

In an aspect, the method can further include providing one or moresensors configured to detect one or more physiological conditions of themammalian subject. The one or more sensors can be configured to detecttissue swelling, tissue pressure, tissue color, tissue temperature,environmental temperature, electrical property of tissue, opticalproperty of tissue, perspiration, or presence of an analyte. The analytecan include an inflammatory marker, antibody, or cytokine.

In an aspect, the method can further include providing one or moresensors configured to determine quality of location or quality ofcontact placement of the one or more sheaths on the one or more bodycontours. In an aspect, the method can further providing include acontroller configured to control release of the one or more medicamentsfrom the one or more applicators. The controller can be configured tocontrol a timed-release dosage of the one or more medicaments. Thecontroller can be configured to report quantity and frequency of dosageof the one or more medicaments. The controller can be configured tocontrol a maximum dosage of the one or more medicaments for a timeperiod. The method can further include providing one or more sensors,wherein the controller is configured to respond to the one or moresensors. The one or more sensors can be configured to detect one or moreconditions at one or more of the one or more joints and the controlleris configured to control release of the one or more medicaments atothers of the one or more joints of the mammalian subject.

The one or more applicators can further include, but are not limited to,tissue permeabilization components including one or more of electronics,ultrasonics, chemical permeation enhancer, iontophoresis, microdialysis,ultrafiltration, electromagnetic, electroosmosis, sonophoresis,microdialysis, suction, electroporation, thermal poration,microporation, heating component, or laser.

The one or more sheaths can include a tourniquet configured to applyintermittent pressure in the region of the jointed area. The tourniquetcan be configured to apply a constricting force thereby causing the oneor more applicators to penetrate the stratum corneum of the skin of themammalian subject.

The method can further include providing a component for transientmechanical/electrical acceleration of the one or more medicaments fromthe high speed microjets. The component for transientmechanical/electrical acceleration can include a fluid displacementactuator configured as one or more piezoelectric actuators, one or moresprings, one or more solenoids, one or more magnets, one or more motors,or one or more compressed gas actuators. The component formechanical/electrical acceleration is configured to apply concentrationgradients of the one or more medicaments in a time-dependent manner.

The one or more medicaments can include, but are not limited to,steroids, corticosteroids, analgesics, COX-2 inhibitors, or NSAIDs. Themethod can further include a pharmaceutical composition including theone or more medicaments in a thixotropic medium. The one or moreapplicators can be configured to apply the one or more medicaments in atime-dependent manner. The one or more applicators can be configured toapply the one or more medicaments in concentration gradients in thetime-dependent manner. The one or more medicaments can be configured tohave a short effective half-life. The one or more medicaments can beconfigured to have a long effective half-life.

A method is described herein that includes providing a device includingone or more sheaths configured to contact one or more body contours inproximity to one or more joints of articulating bone of the mammaliansubject; and one or more microjet applicators supported by the one ormore sheaths and configured to inject one or more medicaments to one ormore joint tissues of the mammalian subject.

A system is described herein that includes at least one apparatusincluding one or more sheaths configured to contact one or more bodycontours in proximity to one or more joints of articulating bone of amammalian subject; and one or more microjet applicators supported by theone or more sheaths and configured to inject one or more medicaments toone or more joint tissues of the mammalian subject. The system canfurther include a recording device configured to collect data regardingone or more physiological conditions of the mammalian subject, and dataregarding administration of the one or more medicaments to the one ormore joint tissues of the mammalian subject. The data can includeinjection sites, medicament types, or medicament administration regimento the mammalian subject. The data regarding the one or morephysiological conditions of the mammalian subject can include movementof the contacted body contour, tissue swelling, tissue pressure, tissuecolor, tissue temperature, environmental temperature, electricalproperty of tissue, optical property of tissue, perspiration, orpresence of an analyte.

A device is described herein that includes one or more substratesconfigured to contact one or more body contours in proximity to one ormore joints of articulating bone of a mammalian subject; one or moresensors configured to monitor movement of the one or more body contours;and one or more applicators supported by the one or more substrates andconfigured to respond to the movement of the one or more body contoursby injecting one or more medicaments to the one or more joint tissues ofthe mammalian subject. The one or more substrates can include, but isnot limited to, one or more patches or one or more sheaths. The one ormore sheaths can include a sleeve-shaped article of clothing or asleeve-shaped body covering. In an aspect, the one or more sheaths caninclude shirt sleeve, pant, leg covering, glove, stocking, bandage-likecovering, brace, knee brace, elbow brace, ankle brace, foot brace, handbrace, or spinal brace. The one or more substrates can be attached tothe one or more body contours by a number of mechanisms including, butnot limited to, glue, suction, suture, or hook. The one or moreapplicators can include one or more high speed microjets, one or moremicroneedles, one or more microfine lances, one or more microfinecannulas, one or more microprojections, or one or more electrodes,wherein the one or more applicators can be supported by the one or moresheaths and can be configured to inject the one or more medicaments tothe one or more joint tissues of the mammalian subject. The one or moreapplicators can include one or more high speed microjets, e.g.,nanoliter-volume pulsed microjets. The one or more applicators canfurther include, but are not limited to, a fluid displacement actuatorconfigured as one or more piezoelectric actuators, one or more springs,one or more solenoids, one or more magnets, one or more motors, or oneor more compressed gas actuators. The one or more applicators includeselectrodes on microprojections configured to apply electrical energy toskin of the mammalian subject. The electrodes on microprojections canprovide ablation of stratum corneum in an area beneath the electrodesthereby generating a plurality of hydrophilic microchannels in the skinof the mammalian subject. In an aspect, the one or more microneedles,the one or more microfine lances, the one or more microfine cannulas, orthe one or more microprojections can contact the one or more jointtissues of the mammalian subject. In an aspect, the one or moreapplicators supported by the one or more sheaths can be configured torespond to one or more sensors, wherein the one or more applicators areconfigured to inject the one or more medicaments to the one or morejoint tissues of the mammalian subject. The one or more joint tissuescan include one or more of a fibrous capsule, subsynovium, synovialmembrane, synovium, joint cavity, synovial fluid, articular cartilage,subchondral bone, or ligament. The one or more joints can include asynovial joint, cartilaginous joint, or fibrous joint.

In an aspect, the device can further include one or more sensorsconfigured to detect movement of the one or more body contours. The oneor more sensors can be configured to monitor joint movement, bodymovement, or gait of the mammalian subject. The one or more sensors canbe configured to monitor posture of the mammalian subject. The one ormore sensors can be configured to monitor frequency of joint use orlevel of effort used by the one or more joints. In a detailed aspect,the level of effort used by the one or more joints includes measuredeffort or inferred effort. The one or more sensors can be configured tomonitor a preselected set of activity profiles.

In an aspect, the device can further include one or more sensorsconfigured to detect one or more physiological conditions of themammalian subject. The one or more sensors can be configured to detecttissue swelling, tissue pressure, tissue color, tissue temperature,environmental temperature, electrical property of tissue, opticalproperty of tissue, perspiration, or presence of an analyte. The analytecan include an inflammatory marker, antibody, or cytokine.

In an aspect, the device can further include one or more sensorsconfigured to determine quality of location or quality of contactplacement of the one or more sheaths on the one or more body contours.

In an aspect, the device can further include a controller configured tocontrol release of the one or more medicaments from the one or moreapplicators. The controller can be configured to control a timed-releasedosage of the one or more medicaments. The controller can be configuredto report quantity and frequency of dosage of the one or moremedicaments. The controller can be configured to control a maximumdosage of the one or more medicaments for a time period. The controllercan be configured to activate the one or more applicators based at leastin part on an activity history of the mammalian subject. In a detailedaspect, the activity history can include joint movement or gait of themammalian subject. The activity history can include, but is not limitedto, frequency of use of the one or more joints, measured effort level ofthe one or more joints, inferred effort level of the one or more joints,or a preselected activity profile. The controller can be configured torespond to the one or more sensors. The one or more sensors can beconfigured to detect one or more conditions at one or more of the one ormore joints and the controller is configured to control release of theone or more medicaments at others of the one or more joints of themammalian subject.

The device can further include a power source. The power source caninclude, but is not limited to, a motion-activated generator, solarcell, fuel cell, wireless source, battery or microbattery. The powersource can be powered by motion of the body of the mammalian subject.

The one or more applicators can further include, but are not limited to,tissue permeabilization components including one or more of electronics,ultrasonics, chemical permeation enhancer, iontophoresis, microdialysis,ultrafiltration, electromagnetic, electroosmosis, sonophoresis,microdialysis, suction, electroporation, thermal poration,microporation, heating component, or laser.

The one or more sheaths can include a tourniquet configured to applyintermittent pressure in the region of the jointed area. The tourniquetcan be configured to apply a constricting force thereby causing the oneor more applicators to penetrate the stratum corneum of the skin of themammalian subject.

The device can further include a component for transientmechanical/electrical acceleration of the one or more medicaments fromthe high speed microjets. The component for transientmechanical/electrical acceleration can include a fluid displacementactuator configured as one or more piezoelectric actuators, one or moresprings, one or more solenoids, one or more magnets, one or more motors,or one or more compressed gas actuators. The component formechanical/electrical acceleration is configured to apply concentrationgradients of the one or more medicaments in a time-dependent manner. Theone or more medicaments can include, but are not limited to, steroids,corticosteroids, analgesics, COX-2 inhibitors, or NSAIDs. The device canfurther include a pharmaceutical composition including the one or moremedicaments in a thixotropic medium. The one or more applicators can beconfigured to apply the one or more medicaments in a time-dependentmanner. The one or more applicators can be configured to apply the oneor more medicaments in concentration gradients in the time-dependentmanner. The one or more medicaments can be configured to have a shorteffective half-life. The one or more medicaments can be configured tohave a long effective half-life.

A method is described herein that includes injecting one or moremedicaments to one or more joint tissues of a mammalian subject, whereinthe injecting of the one or more medicaments is via a device includingone or more substrates configured to contact one or more body contoursin proximity to one or more joints of articulating bone of a mammaliansubject; one or more sensors configured to monitor movement of the oneor more body contours; and one or more applicators supported by the oneor more substrates and configured to respond to the movement of the oneor more body contours by injecting one or more medicaments to the one ormore joint tissues of the mammalian subject. The one or more substratescan include, but is not limited to, one or more patches or one or moresheaths. The one or more sheaths can include a sleeve-shaped article ofclothing or a sleeve-shaped body covering. In an aspect, the one or moresheaths can include shirt sleeve, pant, leg covering, glove, stocking,bandage-like covering, brace, knee brace, elbow brace, ankle brace, footbrace, hand brace, or spinal brace. The one or more applicators caninclude one or more high speed microjets, one or more microneedles, oneor more microfine lances, one or more microfine cannulas, one or moremicroprojections, or one or more electrodes, wherein the one or moreapplicators can be supported by the one or more sheaths and can beconfigured to inject the one or more medicaments to the one or morejoint tissues of the mammalian subject. The one or more applicators caninclude one or more high speed microjets, e.g., nanoliter-volume pulsedmicrojets. The one or more applicators can further include, but are notlimited to, a fluid displacement actuator configured as one or morepiezoelectric actuators, one or more springs, one or more solenoids, oneor more magnets, one or more motors, or one or more compressed gasactuators. The one or more applicators includes electrodes onmicroprojections configured to apply electrical energy to skin of themammalian subject. The electrodes on microprojections can provideablation of stratum corneum in an area beneath the electrodes therebygenerating a plurality of hydrophilic microchannels in the skin of themammalian subject. In an aspect, the one or more microneedles, the oneor more microfine lances, the one or more microfine cannulas, or the oneor more microprojections can contact the one or more joint tissues ofthe mammalian subject. In an aspect, the one or more applicatorssupported by the one or more sheaths can be configured to respond to oneor more sensors, wherein the one or more applicators are configured toinject the one or more medicaments to the one or more joint tissues ofthe mammalian subject. The one or more joint tissues can include one ormore of a fibrous capsule, subsynovium, synovial membrane, synovium,joint cavity, synovial fluid, articular cartilage, subchondral bone, orligament. The one or more joints can include a synovial joint,cartilaginous joint, or fibrous joint.

In an aspect, the method can further include providing one or moresensors configured to detect movement of the one or more body contours.The one or more sensors can be configured to monitor joint movement,body movement, or gait of the mammalian subject. The one or more sensorscan be configured to monitor posture of the mammalian subject. The oneor more sensors can be configured to monitor frequency of joint use orlevel of effort used by the one or more joints. In a detailed aspect,the level of effort used by the one or more joints includes measuredeffort or inferred effort. The one or more sensors can be configured tomonitor a preselected set of activity profiles.

In an aspect, the method can further include providing one or moresensors configured to detect one or more physiological conditions of themammalian subject. The one or more sensors can be configured to detecttissue swelling, tissue pressure, tissue color, tissue temperature,environmental temperature, electrical property of tissue, opticalproperty of tissue, perspiration, or presence of an analyte. The analytecan include an inflammatory marker, antibody, or cytokine.

In an aspect, the method can further include providing one or moresensors configured to determine quality of location or quality ofcontact placement of the one or more sheaths on the one or more bodycontours.

In an aspect, the method can further include providing a controllerconfigured to control release of the one or more medicaments from theone or more applicators. The controller can be configured to control atimed-release dosage of the one or more medicaments. The controller canbe configured to report quantity and frequency of dosage of the one ormore medicaments. The controller can be configured to control a maximumdosage of the one or more medicaments for a time period. The controllercan be configured to activate the one or more applicators based at leastin part on an activity history of the mammalian subject. In a detailedaspect, the activity history can include joint movement or gait of themammalian subject. The activity history can include, but is not limitedto, frequency of use of the one or more joints, measured effort level ofthe one or more joints, inferred effort level of the one or more joints,or a preselected activity profile. The controller can be configured torespond to the one or more sensors. The one or more sensors can beconfigured to detect one or more conditions at one or more of the one ormore joints and the controller is configured to control release of theone or more medicaments at others of the one or more joints of themammalian subject.

The method can further include providing a power source. The powersource can include, but is not limited to, a motion-activated generator,solar cell, fuel cell, wireless source, battery or microbattery. Thepower source can be powered by motion of the body of the mammaliansubject.

The one or more applicators can further include, but are not limited to,tissue permeabilization components including one or more of electronics,ultrasonics, chemical permeation enhancer, iontophoresis, microdialysis,ultrafiltration, electromagnetic, electroosmosis, sonophoresis,microdialysis, suction, electroporation, thermal poration,microporation, heating component, or laser.

The one or more sheaths can include a tourniquet configured to applyintermittent pressure in the region of the jointed area. The tourniquetcan be configured to apply a constricting force thereby causing the oneor more applicators to penetrate the stratum corneum of the skin of themammalian subject.

The method can further include providing a component for transientmechanical/electrical acceleration of the one or more medicaments fromthe high speed microjets. The component for transientmechanical/electrical acceleration can include a fluid displacementactuator configured as one or more piezoelectric actuators, one or moresprings, one or more solenoids, one or more magnets, one or more motors,or one or more compressed gas actuators. The component formechanical/electrical acceleration is configured to apply concentrationgradients of the one or more medicaments in a time-dependent manner. Theone or more medicaments can include, but are not limited to, steroids,corticosteroids, analgesics, COX-2 inhibitors, or NSAIDs. The method canfurther include providing a pharmaceutical composition including the oneor more medicaments in a thixotropic medium. The one or more applicatorscan be configured to apply the one or more medicaments in atime-dependent manner. The one or more applicators can be configured toapply the one or more medicaments in concentration gradients in thetime-dependent manner. The one or more medicaments can be configured tohave a short effective half-life. The one or more medicaments can beconfigured to have a long effective half-life.

A method is described herein that includes providing a device includingone or more substrates configured to contact one or more body contoursin proximity to one or more joints of articulating bone of a mammaliansubject; one or more sensors configured to monitor movement of the oneor more body contours; and one or more applicators supported by the oneor more substrates and configured to respond to the movement of the oneor more body contours by injecting one or more medicaments to the one ormore joint tissues of the mammalian subject.

A system is described herein that includes at least one apparatusincluding one or more substrates configured to contact one or more bodycontours in proximity to one or more joints of articulating bone of amammalian subject; one or more sensors configured to monitor movement ofthe one or more body contours; and one or more applicators supported bythe one or more substrates and configured to respond to the movement ofthe one or more body contours by injecting one or more medicaments tothe one or more joint tissues of the mammalian subject.

A device is described herein that includes one or more substratesconfigured to contact one or more body contours in proximity to one ormore joints of articulating bone of a mammalian subject; one or moresensors configured to detect one or more physiological conditions of theone or more joints; and one or more microjet applicators supported bythe one or more substrates and configured to respond to the one or moresensors by injecting one or more medicaments to the one or more jointtissues of the mammalian subject. The one or more applicators caninclude one or more high speed microjets, e.g., nanoliter-volume pulsedmicrojets. The one or more substrates can include, but is not limitedto, one or more patches or one or more sheaths. The one or more sheathscan include a sleeve-shaped article of clothing or a sleeve-shaped bodycovering. In an aspect, the one or more sheaths can include shirtsleeve, pant, leg covering, glove, stocking, bandage-like covering,brace, knee brace, elbow brace, ankle brace, foot brace, hand brace, orspinal brace. The one or more substrates can be attached to the one ormore body contours by a number of mechanisms including, but not limitedto, glue, suction, suture, or hook.

The one or more applicators can further include, but are not limited to,a fluid displacement actuator configured as one or more piezoelectricactuators, one or more springs, one or more solenoids, one or moremagnets, one or more motors, or one or more compressed gas actuators. Inan aspect, the one or more applicators supported by the one or moresheaths can be configured to respond to one or more sensors, wherein theone or more applicators are configured to inject the one or moremedicaments to the one or more joint tissues of the mammalian subject.

In an aspect, the device can further include one or more sensorsconfigured to detect movement of the one or more body contours. The oneor more sensors can be configured to monitor joint movement, bodymovement, or gait of the mammalian subject. The one or more sensors canbe configured to monitor posture of the mammalian subject. The one ormore sensors can be configured to monitor frequency of joint use orlevel of effort used by the one or more joints. In a detailed aspect,the level of effort used by the one or more joints includes measuredeffort or inferred effort. The one or more sensors can be configured tomonitor a preselected set of activity profiles. In an aspect, the one ormore sensors, configured to detect one or more physiological conditionsof the mammalian subject, can further be configured to detect tissueswelling, tissue pressure, tissue color, tissue temperature,environmental temperature, electrical property of tissue, opticalproperty of tissue, perspiration, or presence of an analyte. The analytecan include an inflammatory marker, antibody, or cytokine. In an aspect,the device can further include one or more sensors configured todetermine quality of location or quality of contact placement of the oneor more sheaths on the one or more body contours.

In an aspect, the device can further include a controller configured tocontrol release of the one or more medicaments from the one or moreapplicators. The controller can be configured to control a timed-releasedosage of the one or more medicaments. The controller can be configuredto report quantity and frequency of dosage of the one or moremedicaments. The controller can be configured to control a maximumdosage of the one or more medicaments for a time period. The controllercan be configured to activate the one or more applicators based at leastin part on an activity history of the mammalian subject. In a detailedaspect, the activity history can include joint movement or gait of themammalian subject. The activity history can include, but is not limitedto, frequency of use of the one or more joints, measured effort level ofthe one or more joints, inferred effort level of the one or more joints,or a preselected activity profile. The device can further include one ormore sensors, wherein the controller is configured to respond to the oneor more sensors. The one or more sensors can be configured to detect oneor more conditions at one or more of the one or more joints and thecontroller is configured to control release of the one or moremedicaments at others of the one or more joints of the mammaliansubject.

The device can further include a power source. The power source caninclude, but is not limited to, a motion-activated generator, solarcell, fuel cell, wireless source, battery or microbattery. The powersource can be powered by motion of the body of the mammalian subject.

The one or more applicators can further include, but are not limited to,tissue permeabilization components including one or more of electronics,ultrasonics, chemical permeation enhancer, iontophoresis, microdialysis,ultrafiltration, electromagnetic, electroosmosis, sonophoresis,microdialysis, suction, electroporation, thermal poration,microporation, heating component, or laser.

The one or more sheaths can include a tourniquet configured to applyintermittent pressure in the region of the jointed area. The tourniquetcan be configured to apply a constricting force thereby causing the oneor more applicators to penetrate the stratum corneum of the skin of themammalian subject.

The device can further include a component for transientmechanical/electrical acceleration of the one or more medicaments fromthe high speed microjets. The component for transientmechanical/electrical acceleration can include a fluid displacementactuator configured as one or more piezoelectric actuators, one or moresprings, one or more solenoids, one or more magnets, one or more motors,or one or more compressed gas actuators. The component formechanical/electrical acceleration is configured to apply concentrationgradients of the one or more medicaments in a time-dependent manner. Theone or more medicaments can include, but are not limited to, steroids,corticosteroids, analgesics, COX-2 inhibitors, or NSAIDs. The device canfurther include a pharmaceutical composition including the one or moremedicaments in a thixotropic medium. The one or more applicators can beconfigured to apply the one or more medicaments in a time-dependentmanner. The one or more applicators can be configured to apply the oneor more medicaments in concentration gradients in the time-dependentmanner. The one or more medicaments can be configured to have a shorteffective half-life. The one or more medicaments can be configured tohave a long effective half-life.

A method is described herein that includes injecting one or moremedicaments to one or more joint tissues of a mammalian subject, whereinthe injecting of the one or more medicaments is via a device includingone or more substrates configured to contact one or more body contoursin proximity to one or more joints of articulating bone of a mammaliansubject; one or more sensors configured to detect one or morephysiological conditions of the one or more joints; and one or moremicrojet applicators supported by the one or more substrates andconfigured to respond to the one or more sensors by injecting one ormore medicaments to the one or more joint tissues of the mammaliansubject.

The one or more applicators can include one or more high speedmicrojets, e.g., nanoliter-volume pulsed microjets. The one or moresubstrates can include, but is not limited to, one or more patches orone or more sheaths. The one or more sheaths can include a sleeve-shapedarticle of clothing or a sleeve-shaped body covering. In an aspect, theone or more sheaths can include shirt sleeve, pant, leg covering, glove,stocking, bandage-like covering, brace, knee brace, elbow brace, anklebrace, foot brace, hand brace, or spinal brace.

The one or more applicators can further include, but are not limited to,a fluid displacement actuator configured as one or more piezoelectricactuators, one or more springs, one or more solenoids, one or moremagnets, one or more motors, or one or more compressed gas actuators. Inan aspect, the one or more applicators supported by the one or moresheaths can be configured to respond to one or more sensors, wherein theone or more applicators are configured to inject the one or moremedicaments to the one or more joint tissues of the mammalian subject.

In an aspect, the method can further include providing one or moresensors configured to detect movement of the one or more body contours.The one or more sensors can be configured to monitor joint movement,body movement, or gait of the mammalian subject. The one or more sensorscan be configured to monitor posture of the mammalian subject. The oneor more sensors can be configured to monitor frequency of joint use orlevel of effort used by the one or more joints. In a detailed aspect,the level of effort used by the one or more joints includes measuredeffort or inferred effort. The one or more sensors can be configured tomonitor a preselected set of activity profiles. In an aspect, the one ormore sensors, configured to detect one or more physiological conditionsof the mammalian subject, can further be configured to detect tissueswelling, tissue pressure, tissue color, tissue temperature,environmental temperature, electrical property of tissue, opticalproperty of tissue, perspiration, or presence of an analyte. The analytecan include an inflammatory marker, antibody, or cytokine. In an aspect,the method can further include providing one or more sensors configuredto determine quality of location or quality of contact placement of theone or more sheaths on the one or more body contours.

In an aspect, the method can further include providing a controllerconfigured to control release of the one or more medicaments from theone or more applicators. The controller can be configured to control atimed-release dosage of the one or more medicaments. The controller canbe configured to report quantity and frequency of dosage of the one ormore medicaments. The controller can be configured to control a maximumdosage of the one or more medicaments for a time period. The controllercan be configured to activate the one or more applicators based at leastin part on an activity history of the mammalian subject. In a detailedaspect, the activity history can include joint movement or gait of themammalian subject. The activity history can include, but is not limitedto, frequency of use of the one or more joints, measured effort level ofthe one or more joints, inferred effort level of the one or more joints,or a preselected activity profile. The method can further includeproviding one or more sensors, wherein the controller is configured torespond to the one or more sensors. The one or more sensors can beconfigured to detect one or more conditions at one or more of the one ormore joints and the controller is configured to control release of theone or more medicaments at others of the one or more joints of themammalian subject.

The method can further include providing a power source. The powersource can include, but is not limited to, a motion-activated generator,solar cell, fuel cell, wireless source, battery or microbattery. Thepower source can be powered by motion of the body of the mammaliansubject.

The one or more applicators can further include, but are not limited to,tissue permeabilization components including one or more of electronics,ultrasonics, chemical permeation enhancer, iontophoresis, microdialysis,ultrafiltration, electromagnetic, electroosmosis, sonophoresis,microdialysis, suction, electroporation, thermal poration,microporation, heating component, or laser.

The one or more sheaths can include a tourniquet configured to applyintermittent pressure in the region of the jointed area. The tourniquetcan be configured to apply a constricting force thereby causing the oneor more applicators to penetrate the stratum corneum of the skin of themammalian subject.

The method can further include providing a component for transientmechanical/electrical acceleration of the one or more medicaments fromthe high speed microjets. The component for transientmechanical/electrical acceleration can include a fluid displacementactuator configured as one or more piezoelectric actuators, one or moresprings, one or more solenoids, one or more magnets, one or more motors,or one or more compressed gas actuators. The component formechanical/electrical acceleration is configured to apply concentrationgradients of the one or more medicaments in a time-dependent manner. Theone or more medicaments can include, but are not limited to, steroids,corticosteroids, analgesics, COX-2 inhibitors, or NSAIDs. The method canfurther include providing a pharmaceutical composition including the oneor more medicaments in a thixotropic medium. The one or more applicatorscan be configured to apply the one or more medicaments in atime-dependent manner. The one or more applicators can be configured toapply the one or more medicaments in concentration gradients in thetime-dependent manner. The one or more medicaments can be configured tohave a short effective half-life. The one or more medicaments can beconfigured to have a long effective half-life.

A method is described herein that includes providing a device includingone or more substrates configured to contact one or more body contoursin proximity to one or more joints of articulating bone of a mammaliansubject; one or more sensors configured to detect one or morephysiological conditions of the one or more joints; and one or moremicrojet applicators supported by the one or more substrates andconfigured to respond to the one or more sensors by injecting one ormore medicaments to the one or more joint tissues of the mammaliansubject.

A system is described herein that includes at least one apparatusincluding one or more substrates configured to contact one or more bodycontours in proximity to one or more joints of articulating bone of amammalian subject; one or more sensors configured to detect one or morephysiological conditions of the one or more joints; and one or moremicrojet applicators supported by the one or more substrates andconfigured to respond to the one or more sensors by injecting one ormore medicaments to the one or more joint tissues of the mammaliansubject.

A device is described herein that includes one or more sheathsconfigured to contact one or more body contours in proximity to one ormore joints of articulating bone of a mammalian subject; one or moresensors configured to detect one or more physiological conditions of theone or more joints; and one or more applicators supported by the one ormore sheaths and configured to respond to the one or more sensors byinjecting one or more medicaments to the one or more joint tissues ofthe mammalian subject. The one or more sheaths can include asleeve-shaped article of clothing or a sleeve-shaped body covering. Inan aspect, the one or more sheaths can include shirt sleeve, pant, legcovering, glove, stocking, bandage-like covering, brace, knee brace,elbow brace, ankle brace, foot brace, hand brace, or spinal brace.

The one or more applicators can include one or more high speedmicrojets, one or more microneedles, one or more microfine lances, oneor more microfine cannulas, one or more microprojections, or one or moreelectrodes, wherein the one or more applicators can be supported by theone or more sheaths and can be configured to inject the one or moremedicaments to the one or more joint tissues of the mammalian subject.The one or more applicators can include one or more high speedmicrojets, e.g., nanoliter-volume pulsed microjets. The one or moreapplicators can further include, but are not limited to, a fluiddisplacement actuator configured as one or more piezoelectric actuators,one or more springs, one or more solenoids, one or more magnets, one ormore motors, or one or more compressed gas actuators. The one or moreapplicators includes electrodes on microprojections configured to applyelectrical energy to skin of the mammalian subject. The electrodes onmicroprojections can provide ablation of stratum corneum in an areabeneath the electrodes thereby generating a plurality of hydrophilicmicrochannels in the skin of the mammalian subject. In an aspect, theone or more microneedles, the one or more microfine lances, the one ormore microfine cannulas, or the one or more microprojections can contactthe one or more joint tissues of the mammalian subject.

In an aspect, the one or more applicators supported by the one or moresheaths can be configured to respond to one or more sensors, wherein theone or more applicators are configured to inject the one or moremedicaments to the one or more joint tissues of the mammalian subject.In an aspect, the device can further include one or more sensorsconfigured to detect movement of the one or more body contours. The oneor more sensors can be configured to monitor joint movement, bodymovement, or gait of the mammalian subject. The one or more sensors canbe configured to monitor posture of the mammalian subject. The one ormore sensors can be configured to monitor frequency of joint use orlevel of effort used by the one or more joints. In a detailed aspect,the level of effort used by the one or more joints includes measuredeffort or inferred effort. The one or more sensors can be configured tomonitor a preselected set of activity profiles. In an aspect, the one ormore sensors, configured to detect one or more physiological conditionsof the mammalian subject, can further be configured to detect tissueswelling, tissue pressure, tissue color, tissue temperature,environmental temperature, electrical property of tissue, opticalproperty of tissue, perspiration, or presence of an analyte. The analytecan include an inflammatory marker, antibody, or cytokine. In an aspect,the device can further include one or more sensors configured todetermine quality of location or quality of contact placement of the oneor more sheaths on the one or more body contours.

In an aspect, the device can further include a controller configured tocontrol release of the one or more medicaments from the one or moreapplicators. The controller can be configured to control a timed-releasedosage of the one or more medicaments. The controller can be configuredto report quantity and frequency of dosage of the one or moremedicaments. The controller can be configured to control a maximumdosage of the one or more medicaments for a time period. The controllercan be configured to activate the one or more applicators based at leastin part on an activity history of the mammalian subject. In a detailedaspect, the activity history can include joint movement or gait of themammalian subject. The activity history can include, but is not limitedto, frequency of use of the one or more joints, measured effort level ofthe one or more joints, inferred effort level of the one or more joints,or a preselected activity profile. The device can further include one ormore sensors, wherein the controller is configured to respond to the oneor more sensors. The one or more sensors can be configured to detect oneor more conditions at one or more of the one or more joints and thecontroller is configured to control release of the one or moremedicaments at others of the one or more joints of the mammaliansubject.

The device can further include a power source. The power source caninclude, but is not limited to, a motion-activated generator, solarcell, fuel cell, wireless source, battery or microbattery. The powersource can be powered by motion of the body of the mammalian subject.

The one or more applicators can further include, but are not limited to,tissue permeabilization components including one or more of electronics,ultrasonics, chemical permeation enhancer, iontophoresis, microdialysis,ultrafiltration, electromagnetic, electroosmosis, sonophoresis,microdialysis, suction, electroporation, thermal poration,microporation, heating component, or laser.

The one or more sheaths can include a tourniquet configured to applyintermittent pressure in the region of the jointed area. The tourniquetcan be configured to apply a constricting force thereby causing the oneor more applicators to penetrate the stratum corneum of the skin of themammalian subject.

The device can further include a component for transientmechanical/electrical acceleration of the one or more medicaments fromthe high speed microjets. The component for transientmechanical/electrical acceleration can include a fluid displacementactuator configured as one or more piezoelectric actuators, one or moresprings, one or more solenoids, one or more magnets, one or more motors,or one or more compressed gas actuators. The component formechanical/electrical acceleration is configured to apply concentrationgradients of the one or more medicaments in a time-dependent manner. Theone or more medicaments can include, but are not limited to, steroids,corticosteroids, analgesics, COX-2 inhibitors, or NSAIDs. The device canfurther include a pharmaceutical composition including the one or moremedicaments in a thixotropic medium. The one or more applicators can beconfigured to apply the one or more medicaments in a time-dependentmanner. The one or more applicators can be configured to apply the oneor more medicaments in concentration gradients in the time-dependentmanner. The one or more medicaments can be configured to have a shorteffective half-life. The one or more medicaments can be configured tohave a long effective half-life.

A method is described herein that includes injecting one or moremedicaments to one or more joint tissues of a mammalian subject, whereinthe injecting of the one or more medicaments is via a device includingone or more sheaths configured to contact one or more body contours inproximity to one or more joints of articulating bone of a mammaliansubject; one or more sensors configured to detect one or morephysiological conditions of the one or more joints; and an applicatorsupported by the one or more sheaths and configured to respond to theone or more sensors by injecting one or more medicaments to the one ormore joint tissues of the mammalian subject. The one or more sheaths caninclude a sleeve-shaped article of clothing or a sleeve-shaped bodycovering. In an aspect, the one or more sheaths can include shirtsleeve, pant, leg covering, glove, stocking, bandage-like covering,brace, knee brace, elbow brace, ankle brace, foot brace, hand brace, orspinal brace.

The one or more applicators can include one or more high speedmicrojets, one or more microneedles, one or more microfine lances, oneor more microfine cannulas, one or more microprojections, or one or moreelectrodes, wherein the one or more applicators can be supported by theone or more sheaths and can be configured to inject the one or moremedicaments to the one or more joint tissues of the mammalian subject.The one or more applicators can include one or more high speedmicrojets, e.g., nanoliter-volume pulsed microjets. The one or moreapplicators can further include, but are not limited to, a fluiddisplacement actuator configured as one or more piezoelectric actuators,one or more springs, one or more solenoids, one or more magnets, one ormore motors, or one or more compressed gas actuators. The one or moreapplicators includes electrodes on microprojections configured to applyelectrical energy to skin of the mammalian subject. The electrodes onmicroprojections can provide ablation of stratum corneum in an areabeneath the electrodes thereby generating a plurality of hydrophilicmicrochannels in the skin of the mammalian subject. In an aspect, theone or more microneedles, the one or more microfine lances, the one ormore microfine cannulas, or the one or more microprojections can contactthe one or more joint tissues of the mammalian subject. In an aspect,the one or more applicators supported by the one or more sheaths can beconfigured to respond to one or more sensors, wherein the one or moreapplicators are configured to inject the one or more medicaments to theone or more joint tissues of the mammalian subject.

In an aspect, the method can further include providing one or moresensors configured to detect movement of the one or more body contours.The one or more sensors can be configured to monitor joint movement,body movement, or gait of the mammalian subject. The one or more sensorscan be configured to monitor posture of the mammalian subject. The oneor more sensors can be configured to monitor frequency of joint use orlevel of effort used by the one or more joints. In a detailed aspect,the level of effort used by the one or more joints includes measuredeffort or inferred effort. The one or more sensors can be configured tomonitor a preselected set of activity profiles. In an aspect, the one ormore sensors, configured to detect one or more physiological conditionsof the mammalian subject, can further be configured to detect tissueswelling, tissue pressure, tissue color, tissue temperature,environmental temperature, electrical property of tissue, opticalproperty of tissue, perspiration, or presence of an analyte. The analytecan include an inflammatory marker, antibody, or cytokine. In an aspect,the method can further include providing one or more sensors configuredto determine quality of location or quality of contact placement of theone or more sheaths on the one or more body contours.

In an aspect, the method can further include providing a controllerconfigured to control release of the one or more medicaments from theone or more applicators. The controller can be configured to control atimed-release dosage of the one or more medicaments. The controller canbe configured to report quantity and frequency of dosage of the one ormore medicaments. The controller can be configured to control a maximumdosage of the one or more medicaments for a time period. The controllercan be configured to activate the one or more applicators based at leastin part on an activity history of the mammalian subject. In a detailedaspect, the activity history can include joint movement or gait of themammalian subject. The activity history can include, but is not limitedto, frequency of use of the one or more joints, measured effort level ofthe one or more joints, inferred effort level of the one or more joints,or a preselected activity profile. The method can further includeproviding one or more sensors, wherein the controller is configured torespond to the one or more sensors. The one or more sensors can beconfigured to detect one or more conditions at one or more of the one ormore joints and the controller is configured to control release of theone or more medicaments at others of the one or more joints of themammalian subject.

The method can further include providing a power source. The powersource can include, but is not limited to, a motion-activated generator,solar cell, fuel cell, wireless source, battery or microbattery. Thepower source can be powered by motion of the body of the mammaliansubject.

The one or more applicators can further include, but are not limited to,tissue permeabilization components including one or more of electronics,ultrasonics, chemical permeation enhancer, iontophoresis, microdialysis,ultrafiltration, electromagnetic, electroosmosis, sonophoresis,microdialysis, suction, electroporation, thermal poration,microporation, heating component, or laser.

The one or more sheaths can include a tourniquet configured to applyintermittent pressure in the region of the jointed area. The tourniquetcan be configured to apply a constricting force thereby causing the oneor more applicators to penetrate the stratum corneum of the skin of themammalian subject.

The method can further include providing a component for transientmechanical/electrical acceleration of the one or more medicaments fromthe high speed microjets. The component for transientmechanical/electrical acceleration can include a fluid displacementactuator configured as one or more piezoelectric actuators, one or moresprings, one or more solenoids, one or more magnets, one or more motors,or one or more compressed gas actuators. The component formechanical/electrical acceleration is configured to apply concentrationgradients of the one or more medicaments in a time-dependent manner. Theone or more medicaments can include, but are not limited to, steroids,corticosteroids, analgesics, COX-2 inhibitors, or NSAIDs. The method canfurther include providing a pharmaceutical composition including the oneor more medicaments in a thixotropic medium. The one or more applicatorscan be configured to apply the one or more medicaments in atime-dependent manner. The one or more applicators can be configured toapply the one or more medicaments in concentration gradients in thetime-dependent manner. The one or more medicaments can be configured tohave a short effective half-life. The one or more medicaments can beconfigured to have a long effective half-life.

A method is described herein that includes providing a device includingone or more sheaths configured to contact one or more body contours inproximity to one or more joints of articulating bone of a mammaliansubject; one or more sensors configured to detect one or morephysiological conditions of the one or more joints; and an applicatorsupported by the one or more sheaths and configured to respond to theone or more sensors by injecting one or more medicaments to the one ormore joint tissues of the mammalian subject. The one or more sheaths caninclude a sleeve-shaped article of clothing or a sleeve-shaped bodycovering. In an aspect, the one or more sheaths can include shirtsleeve, pant, leg covering, glove, stocking, bandage-like covering,brace, knee brace, elbow brace, ankle brace, foot brace, hand brace, orspinal brace.

A system is described herein that includes at least one apparatusincluding one or more sheaths configured to contact one or more bodycontours in proximity to one or more joints of articulating bone of amammalian subject; one or more sensors configured to detect one or morephysiological conditions of the one or more joints; and one or moreapplicators supported by the one or more sheaths and configured torespond to the one or more sensors by injecting one or more medicamentsto the one or more joint tissues of the mammalian subject.

A device is described herein that includes an enclosure including one ormore sensors, a controller, and one or more applicators configured tosurround one or more joints of articulating bone of a mammalian subject,wherein the one or more sensors are configured to detect one or morephysiological conditions of the one or more joints of the mammaliansubject, and the controller, configured to communicate with the one ormore sensors, is configured to activate the one or more applicators, andwherein the one or more applicators are configured to inject one or moremedicaments to one or more joint tissues of the mammalian subject.

The one or more sensors can be configured to detect a physiologicalcondition including, but not limited to, tissue swelling, tissuepressure, tissue color, tissue temperature, environmental temperature,electrical property of tissue, optical property of tissue, perspiration,or presence of an analyte. The analyte can include an inflammatorymarker, antibody, or cytokine. The one or more applicators can includeone or more high speed microjets, one or more microneedles, one or moremicrofine lances, one or more microfine cannulas, one or moremicroprojections, or one or more electrodes, wherein the one or moreapplicators can be supported by the one or more sheaths and can beconfigured to inject the one or more medicaments to the one or morejoint tissues of the mammalian subject. The one or more applicators caninclude one or more high speed microjets, e.g., nanoliter-volume pulsedmicrojets. The one or more applicators can further include, but are notlimited to, a fluid displacement actuator configured as one or morepiezoelectric actuators, one or more springs, one or more solenoids, oneor more magnets, one or more motors, or one or more compressed gasactuators. The one or more applicators includes electrodes onmicroprojections configured to apply electrical energy to skin of themammalian subject. The electrodes on microprojections can provideablation of stratum corneum in an area beneath the electrodes therebygenerating a plurality of hydrophilic microchannels in the skin of themammalian subject. In an aspect, the one or more microneedles, the oneor more microfine lances, the one or more microfine cannulas, or the oneor more microprojections can contact the one or more joint tissues ofthe mammalian subject. In an aspect, the one or more applicators can beconfigured to respond to one or more sensors, wherein the one or moreapplicators are configured to inject the one or more medicaments to theone or more joint tissues of the mammalian subject. The one or morejoint tissues can include one or more of a fibrous capsule, subsynovium,synovial membrane, synovium, joint cavity, synovial fluid, articularcartilage, subchondral bone, or ligament. The one or more joints caninclude a synovial joint, cartilaginous joint, or fibrous joint.

In an aspect, the device can further include one or more sensorsconfigured to detect movement of the one or more body contours. The oneor more sensors can be configured to monitor joint movement, bodymovement, or gait of the mammalian subject. The one or more sensors canbe configured to monitor posture of the mammalian subject. The one ormore sensors can be configured to monitor frequency of joint use orlevel of effort used by the one or more joints. In a detailed aspect,the level of effort used by the one or more joints includes measuredeffort or inferred effort. The one or more sensors can be configured tomonitor a preselected set of activity profiles.

In an aspect, the device can further include a controller configured tocontrol release of the one or more medicaments from the one or moreapplicators. The controller can be configured to control a timed-releasedosage of the one or more medicaments. The controller can be configuredto report quantity and frequency of dosage of the one or moremedicaments. The controller can be configured to control a maximumdosage of the one or more medicaments for a time period. The controllercan be configured to activate the one or more applicators based at leastin part on an activity history of the mammalian subject. In a detailedaspect, the activity history can include joint movement or gait of themammalian subject. The activity history can include, but is not limitedto, frequency of use of the one or more joints, measured effort level ofthe one or more joints, inferred effort level of the one or more joints,or a preselected activity profile. The controller can be configured torespond to the one or more sensors. The one or more sensors can beconfigured to detect one or more conditions at one or more of the one ormore joints and the controller is configured to control release of theone or more medicaments at others of the one or more joints of themammalian subject. In an aspect, the one or more sensors are configuredto detect one or more physiological conditions of the mammalian subject.In a further aspect, the one or more sensors are configured to detectmovement of the one or more body contours.

The device can further include a power source. The power source caninclude, but is not limited to, a motion-activated generator, solarcell, fuel cell, wireless source, battery, microbattery, or wiredsource.

The one or more applicators can further include, but are not limited to,tissue permeabilization components including one or more of electronics,ultrasonics, chemical permeation enhancer, iontophoresis, microdialysis,ultrafiltration, electromagnetic, electroosmosis, sonophoresis,microdialysis, suction, electroporation, thermal poration,microporation, heating component, or laser. The chemical permeationenhancer can include, but is not limited to, a dermal penetrationenhancer including one or more esters including long chain alkylpara-aminobenzoate, long chain alkyl dimethyl-para-aminobenzoate, longchain alkyl cinnamate, long chain alkyl methoxycinnamate, long chainalkyl salicylate, octyl dimethyl-para-aminobenzoate, octylpara-methoxycinnamate, or octyl salicylate

The enclosure can include a tourniquet configured to apply intermittentpressure in the region of the jointed area. The tourniquet can beconfigured to apply a constricting force thereby causing the one or moreapplicators to penetrate the stratum corneum of the skin of themammalian subject.

The device can further include a component for transientmechanical/electrical acceleration of the one or more medicaments fromthe high speed microjets. The component for transientmechanical/electrical acceleration can include a fluid displacementactuator configured as one or more piezoelectric actuators, one or moresprings, one or more solenoids, one or more magnets, one or more motors,or one or more compressed gas actuators. The component formechanical/electrical acceleration is configured to apply concentrationgradients of the one or more medicaments in a time-dependent manner. Theone or more medicaments can include, but are not limited to, steroids,corticosteroids, analgesics, COX-2 inhibitors, or NSAIDs. The device canfurther include a pharmaceutical composition including the one or moremedicaments in a thixotropic medium. The one or more applicators can beconfigured to apply the one or more medicaments in a time-dependentmanner. The one or more applicators can be configured to apply the oneor more medicaments in concentration gradients in the time-dependentmanner. The one or more medicaments can be configured to have a shorteffective half-life. The one or more medicaments can be configured tohave a long effective half-life.

A method is described herein that includes injecting one or moremedicaments to one or more joint tissues of a mammalian subject, whereinthe injecting of the one or more medicaments is via a device includingan enclosure including one or more sensors, a controller, and one ormore applicators configured to surround one or more joints ofarticulating bone of a mammalian subject, wherein the one or moresensors are configured to detect one or more physiological conditions ofthe one or more joints of the mammalian subject, and the controller,configured to communicate with the one or more sensors, is configured toactivate the one or more applicators, and wherein the one or moreapplicators are configured to inject one or more medicaments to one ormore joint tissues of the mammalian subject.

The one or more sensors can be configured to detect a physiologicalcondition including, but not limited to, tissue swelling, tissuepressure, tissue color, tissue temperature, environmental temperature,electrical property of tissue, optical property of tissue, perspiration,or presence of an analyte. The analyte can include an inflammatorymarker, antibody, or cytokine. The one or more applicators can includeone or more high speed microjets, one or more microneedles, one or moremicrofine lances, one or more microfine cannulas, one or moremicroprojections, or one or more electrodes, wherein the one or moreapplicators can be supported by the one or more sheaths and can beconfigured to inject the one or more medicaments to the one or morejoint tissues of the mammalian subject. The one or more applicators caninclude one or more high speed microjets, e.g., nanoliter-volume pulsedmicrojets. The one or more applicators can further include, but are notlimited to, a fluid displacement actuator configured as one or morepiezoelectric actuators, one or more springs, one or more solenoids, oneor more magnets, one or more motors, or one or more compressed gasactuators. The one or more applicators includes electrodes onmicroprojections configured to apply electrical energy to skin of themammalian subject. The electrodes on microprojections can provideablation of stratum corneum in an area beneath the electrodes therebygenerating a plurality of hydrophilic microchannels in the skin of themammalian subject. In an aspect, the one or more microneedles, the oneor more microfine lances, the one or more microfine cannulas, or the oneor more microprojections can contact the one or more joint tissues ofthe mammalian subject. In an aspect, the one or more applicators can beconfigured to respond to one or more sensors, wherein the one or moreapplicators are configured to inject the one or more medicaments to theone or more joint tissues of the mammalian subject. The one or morejoint tissues can include one or more of a fibrous capsule, subsynovium,synovial membrane, synovium, joint cavity, synovial fluid, articularcartilage, subchondral bone, or ligament. The one or more joints caninclude a synovial joint, cartilaginous joint, or fibrous joint.

In an aspect, the method can further include providing one or moresensors configured to detect movement of the one or more body contours.The one or more sensors can be configured to monitor joint movement,body movement, or gait of the mammalian subject. The one or more sensorscan be configured to monitor posture of the mammalian subject. The oneor more sensors can be configured to monitor frequency of joint use orlevel of effort used by the one or more joints. In a detailed aspect,the level of effort used by the one or more joints includes measuredeffort or inferred effort. The one or more sensors can be configured tomonitor a preselected set of activity profiles.

In an aspect, the providing can further include providing a controllerconfigured to control release of the one or more medicaments from theone or more applicators. The controller can be configured to control atimed-release dosage of the one or more medicaments. The controller canbe configured to report quantity and frequency of dosage of the one ormore medicaments. The controller can be configured to control a maximumdosage of the one or more medicaments for a time period. The controllercan be configured to activate the one or more applicators based at leastin part on an activity history of the mammalian subject. In a detailedaspect, the activity history can include joint movement or gait of themammalian subject. The activity history can include, but is not limitedto, frequency of use of the one or more joints, measured effort level ofthe one or more joints, inferred effort level of the one or more joints,or a preselected activity profile. The controller can be configured torespond to the one or more sensors. The one or more sensors can beconfigured to detect one or more conditions at one or more of the one ormore joints and the controller is configured to control release of theone or more medicaments at others of the one or more joints of themammalian subject. In an aspect, the one or more sensors are configuredto detect one or more physiological conditions of the mammalian subject.In a further aspect, the one or more sensors are configured to detectmovement of the one or more body contours.

The method can further include providing a power source. The powersource can include, but is not limited to, a motion-activated generator,solar cell, fuel cell, wireless source, battery, microbattery, or wiredsource.

The one or more applicators can further include, but are not limited to,tissue permeabilization components including one or more of electronics,ultrasonics, chemical permeation enhancer, iontophoresis, microdialysis,ultrafiltration, electromagnetic, electroosmosis, sonophoresis,microdialysis, suction, electroporation, thermal poration,microporation, heating component, or laser. The chemical permeationenhancer can include, but is not limited to, a dermal penetrationenhancer including one or more esters including long chain alkylpara-aminobenzoate, long chain alkyl dimethyl-para-aminobenzoate, longchain alkyl cinnamate, long chain alkyl methoxycinnamate, long chainalkyl salicylate, octyl dimethyl-para-aminobenzoate, octylpara-methoxycinnamate, or octyl salicylate

The enclosure can include a tourniquet configured to apply intermittentpressure in the region of the jointed area. The tourniquet can beconfigured to apply a constricting force thereby causing the one or moreapplicators to penetrate the stratum corneum of the skin of themammalian subject.

The method can further include providing a component for transientmechanical/electrical acceleration of the one or more medicaments fromthe high speed microjets. The component for transientmechanical/electrical acceleration can include a fluid displacementactuator configured as one or more piezoelectric actuators, one or moresprings, one or more solenoids, one or more magnets, one or more motors,or one or more compressed gas actuators. The component formechanical/electrical acceleration is configured to apply concentrationgradients of the one or more medicaments in a time-dependent manner. Theone or more medicaments can include, but are not limited to, steroids,corticosteroids, analgesics, COX-2 inhibitors, or NSAIDs. The device canfurther include a pharmaceutical composition including the one or moremedicaments in a thixotropic medium. The one or more applicators can beconfigured to apply the one or more medicaments in a time-dependentmanner. The one or more applicators can be configured to apply the oneor more medicaments in concentration gradients in the time-dependentmanner. The one or more medicaments can be configured to have a shorteffective half-life. The one or more medicaments can be configured tohave a long effective half-life.

A method is described herein that includes providing a device includingan enclosure including one or more sensors, a controller, and one ormore applicators configured to surround one or more joints ofarticulating bone of a mammalian subject, wherein the one or moresensors are configured to detect one or more physiological conditions ofthe one or more joints of the mammalian subject, and the controller,configured to communicate with the one or more sensors, is configured toactivate the one or more applicators, and wherein the one or moreapplicators are configured to inject one or more medicaments to one ormore joint tissues of the mammalian subject.

A system is described herein that includes at least one apparatusincluding an enclosure including one or more sensors, a controller, andone or more applicators configured to surround one or more joints ofarticulating bone of a mammalian subject, wherein the one or moresensors are configured to detect one or more physiological conditions ofthe one or more joints of the mammalian subject, and the controller,configured to communicate with the one or more sensors, is configured toactivate the one or more applicators, and wherein the one or moreapplicators are configured to inject one or more medicaments to one ormore joint tissues of the mammalian subject.

The foregoing summary is illustrative only and is not intended to be inany way limiting. In addition to the illustrative aspects, embodiments,and features described above, an aspect, embodiments, and features willbecome apparent by reference to the drawings and the following detaileddescription.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a diagrammatic view of an aspect of a device.

FIG. 2 depicts a diagrammatic view of an aspect of a device.

FIG. 3 depicts a diagrammatic view of an aspect of a knee joint.

FIG. 4 illustrates an exemplary method that includes injecting one ormore medicaments to one or more joint tissues of a mammalian subject viaa device.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components, unless contextdictates otherwise. The illustrative embodiments described in thedetailed description, drawings, and claims are not meant to be limiting.Other embodiments may be utilized, and other changes may be made,without departing from the spirit or scope of the subject matterpresented here.

The present application uses formal outline headings for clarity ofpresentation. However, it is to be understood that the outline headingsare for presentation purposes, and that different types of subjectmatter may be discussed throughout the application (e.g., method(s) maybe described under composition heading(s) and/or kit headings; and/ordescriptions of single topics may span two or more topic headings).Hence, the use of the formal outline headings is not intended to be inany way limiting.

A device is described for treating a disease or a condition of one ormore joints of articulating bone in a mammalian subject. The deviceprovides one or more medicaments to one or more joints of the mammaliansubject. A device is described for treating a disease or a condition ofone or more joints of articulating bone in a mammalian subject. Thedevice provides one or more medicaments to one or more joints of themammalian subject. A device is described herein that includes one ormore sheaths configured to contact one or more body contours inproximity to one or more joints of articulating bone of a mammaliansubject; and one or more microjet applicators supported by the one ormore sheaths and configured to inject one or more medicaments to one ormore joint tissues of the mammalian subject. The one or more applicatorscan include one or more high speed microjets, e.g., nanoliter-volumepulsed microjets. The one or more sheaths can include a sleeve-shapedarticle of clothing or a sleeve-shaped body covering. In an aspect, theone or more sheaths can include shirt sleeve, pant, leg covering, glove,stocking, bandage-like covering, brace, knee brace, elbow brace, anklebrace, foot brace, hand brace, or spinal brace. The sheath can includean article of clothing including, but not limited to, a partial or fullarticle of clothing, e.g., a partial glove that covers two or morefingers or a full glove that covers a hand; a ¾ length sleeve, or a fulllength sleeve. The one or more substrates can be attached to the one ormore body contours by a number of mechanisms including, but not limitedto, glue, suction, suture, or hook. The one or more joints can include asynovial joint, cartilaginous joint, or fibrous joint. In an aspect, theone or more applicators supported by the one or more sheaths can beconfigured to respond to one or more sensors, wherein the one or moreapplicators are configured to inject the one or more medicaments to theone or more joint tissues of the mammalian subject.

In an aspect, the applicator includes one or more high speed microjets,one or more microneedles, one or more microfine lances, one or moremicrofine cannulas, one or more microprojections, or one or moreelectrodes. In an aspect, the applicator includes a fluid displacementactuator configured as one or more piezoelectric actuators, one or moresprings, one or more solenoids, one or more magnets, one or more motors,or one or more compressed gas actuators.

In an aspect, the device can include medicament applicators includingone or more high speed microjets. High speed microjets can deliver oneor more medicaments by displacing the medicament solution through amicronozzle, e.g., 50-100 μm in final diameter. The high speed microjetscan use one or more modes of fluid displacement, e.g., a piezoelectricactuator displacing a plunger, that provides a device or system havingrobustness and energy efficiency. The displacement of the plunger by thepiezoelectric actuator can eject a microjet whose volume and velocitycan be controlled by controlling the voltage and the rise time of theapplied pulse to the piezoelectric actuator. At the end of the stroke,the plunger can be brought back to its original position by a compressedspring. The voltage applied to the piezoelectric crystal can be variedbetween 0 and 140 V to generate microjets with volumes up to 15nanoliters. The frequency of pulses can be within a range of 0.1 to 10Hz, e.g., 1 Hz. The medicament solution can be filled in a reservoir,which directly feeds the solution to the micronozzle of the microjet.The reservoir can be maintained at a slight overpressure, e.g., a smallfraction of atmospheric pressure, to avoid backflow. In detailedaspects, the piezoelectric actuator, on application of a voltage pulse,can expand rapidly to push a plunger that ejects the fluid from themicronozzle as a high-speed microjet. The volume of the microjet isproportional to the amplitude of the voltage pulse, and the velocity ofthe microjet is proportional to the rise time. In further detailedaspects, a rise time of 10 μseconds would lead to a mean velocity of 127meters/second for a 10-nanoliter microjet delivered from a 100-μmdiameter micronozzle. For example, ν=Q/At, where Q is the microjetvolume, A is the cross-sectional area of the micronozzle, and t is therise time. By controlling the amplitude and rise time of the pulse,velocity as well as volume of the microjet can be adjusted. Dispensedvolume from the nozzle is replaced by liquid from the reservoir, whichis maintained under slight positive pressure to avoid backflow. Undertypical operating conditions, microjets can be ejected from themicronozzle at exit velocities exceeding 100 meters/second and volumesof 10 to 15 nanoliters. The microjets can be cylindrical in shape andeach jet pulse could be clearly distinguished. To deliver volumes inexcess of 10 to 15 nanoliters, the microjets can be designed to operateover a prolonged time period, and the total amount of liquid ejectedwill be proportional to the application time. In an aspect, a pulsationfrequency of 1 Hz (1 microjet per second) can be used. This frequencycan be increased if higher delivery rates are desired. See, e.g., Aroraet al., Proc. Natl. Acad. Sci. USA, 104: 4255-4260, 2007, which isincorporated herein by reference. Other modes of fluid displacement fromthe high speed microjet include, but are not limited to, dielectricbreakdown, electromagnetic displacement, springs, solenoids, motors, orcompressed gas actuators.

In an aspect, the device includes medicament applicators including oneor more microneedles that can be produced by microfabricationtechnology. Microneedles can be used to deliver the one or moremedicaments through the stratum corneum barrier of the mammaliansubject. The microneedles pierce into the skin to permit drug delivery,and are short and thin to avoid causing pain. The stratum corneum at theskin surface of the mammalian subject provides a barrier to drugtransport into the body of the mammalian subject. A microneedle can beconfigured to cross the stratum corneum and deliver drugs into thepermeable regions of skin without stimulating nerves found deeper in thetissue. Microneedles can be configured to pierce human skin and toincrease, by two or more orders of magnitude and over time, skinpermeability to small molecules and proteins. See, e.g., Kaushik et al.,Anesth. Analg., 92: 502-504, 2001; Henry S, et al., J Pharm Sci., 87:922-925, 1998; McAllister D, et al., Proc Int Symp Control Rel BioactMater., 26: 192-193, 1999, each of which is incorporated herein byreference. In an aspect, the device including medicament applicators canbe microfabricated as one or more microfine lances, one or moremicrofine cannulas, or one or more microprojections.

In an aspect, devices including solid microneedles can be used incombination with transdermal patch technology. Integrated into a patch,microneedles can provide a minimally invasive method to increase skinpermeability for diffusion-based transport that could make transdermaldelivery of many drugs possible, including that of large molecules suchas proteins. Hollow microneedles, either as individual needles or asmultineedle arrays, can be used for convection-based delivery. Thismicroinfusion approach can increase rates of delivery beyond those ofpassive patches, and permit rates to be modulated in real time by amicroprocessor-controlled pump, which can include a user interface forinput by patients or by healthcare providers, or by a companion animalowner, animal caretaker or a livestock owner. See, e.g., McAllister etal., Proc. Natl. Acad. Sci. USA, 100: 13755-13760, 2003, which isincorporated herein by reference.

In an aspect, the device includes medicament applicators including oneor more electrodes on microprojections configured to apply electricalenergy to skin of the mammalian subject. The electrodes onmicroprojections provide ablation of stratum corneum in an area beneaththe electrodes thereby generating a plurality of hydrophilicmicrochannels in the skin of the mammalian subject. The one or moremedicaments can be delivered through the plurality of hydrophilicmicrochannels in the skin of the mammalian subject. See, e.g., U.S. Pat.No. 7,395,111; or U.S. 2005/0226922, each of which is incorporatedherein by reference.

Piezoelectric actuators can be configured to displace plungers in thehigh speed microjets. The piezoelectric actuators can include capacitivetransducers that expand when voltage is applied to them. Thedisplacements of piezoelectric actuators are typically small (e.g.,typically less than 10 μm), while the forces they generate can be quitelarge, from approximately 1 N to approximately 1000 N. Typically, theexpansion of a piezoelectric actuator is limited by size, but largedisplacements which result in larger velocities can be desirable. Oneway to amplify the motion of a piezoelectric actuator is to use flexuralhinges. Expansion of the piezoelectric actuator in the horizontaldirection (x-x) can lead to a push or pull of hinges in the verticaldirection (y-y). See, e.g., U.S. 2008/0091139, which is incorporatedherein by reference

In an aspect, the device includes the applicator configured as acompressed gas actuator to pressurize the chamber for delivery of theone or more medicaments through one or more high speed microjets. Acompressed gas actuator is necessary to pressurize the central apertureof the one or more high speed microjets. The compressed gas actuator cantake the form of a gas canister linked to a button cylinder, withoperation of the button cylinder releasing a fixed amount of gas, forexample 5 ml, enabling the gas source to be used to deliver sequentiallya plurality of discrete payloads of one or more medicaments withoutneeding to be recharged. Alternatively, a closed gas cylinder containinga single dose of gas can be sufficient for a single medicament deliveryfrom the one or more high speed microjets. The gas source can include,e.g., helium, with the gas cylinder containing helium gas at a pressureof between approximately 15 bar and approximately 35 bar, or around 30bar. Helium, as a driver gas, can provide much higher gas velocity thanair, nitrogen, or CO₂.

In an aspect, the device includes an applicator supported by one or moresheaths and configured to inject one or more medicaments to a tissue ofthe one or more joints of the mammalian subject. The one or more sheathscan be configured to contact a body contour at one or more joints ofarticulating bone of the mammalian subject. The one or more sheaths canbe a sleeve-shaped article of clothing or a sleeve-shaped body coveringfor one or more joints of articulating bone. The one or more sheathsincluding the one or more medicament applicators is aligned to the oneor more joints of the mammalian subject, e.g., hand, wrist, elbow,shoulder, neck, foot, ankle, knee, or hip. The sheath or brace isaligned to surface architecture of the one or more joints of themammalian subject. The sheath or brace can be held in a fixed positionsurrounding the joint by a variety of attachment mechanisms, e.g.,elastic, adhesive, or Velcro® hook and loop fastener. The applicator candeliver concentrated therapeutic medicaments directly to tissues of theone or more joints including one or more of a fibrous capsule,subsynovium, synovial membrane, synovium, joint cavity, synovial fluid,articular cartilage, subchondral bone, or ligament of the joint of themammalian subject.

In an aspect, the device including the one or more sheaths can alsoinclude a pressure-exerting device or tourniquet to apply a constrictingforce and/or pressure on the applicator, e.g., microneedles, to ensurepenetration of the stratum corneum of the mammalian subject. The deviceincluding the one or more sheaths can further apply pressure to themicroneedles to ensure penetration of the microneedles directly into theone or more joint tissues including one or more of a fibrous capsule,subsynovium, synovial membrane, synovium, joint cavity, synovial fluid,articular cartilage, subchondral bone, and/or ligaments. See, e.g., U.S.2009/0155341, which is incorporated herein by reference.

Delivery of the one or more medicaments to the one or more joints viathe applicator can include a controller including a manually-activatedswitch. The manually activated switch can provide electric current tothe applicator. This can be done “as needed” for pain and stiffness asdetermined by the mammalian subject, by a health care provider, or by acompanion animal owner, animal caretaker or a livestock owner. The doseof one or more medicaments delivered can be determined by theconcentration of the one or more medicaments in the reservoir and theduration of the electric current from the activated switch. A sensorincluding micro-circuitry can monitor the total dose of the one or moremedicaments delivered within 24 hours and control drug delivery toprevent exceeding the maximum recommended dose to the mammalian subject.The device can include a controller in communication with the one ormore sheaths via a sensor including micro-circuitry. The sensorincluding micro-circuitry can include a timer that allows the mammaliansubject or a healthcare worker to program a dose and schedule fordelivery of the one or more medicaments. The dosing schedule can spanhours, days, weeks or months and the micro-circuitry can record andstore total dosage and/or dosage within a fixed time period of hours,days, weeks or months. The device can transmit information through thesensor and the controller, including, but not limited to, drug dosage,schedule, and drug consumption to a computer network system that can beaccessible by the mammalian subject, the subject's family, healthcareproviders, insurance companies, regulatory authorities or public healthofficials.

In an aspect, the device including one or more sheaths configured tocontact a body contour at one or more joints of articulating bone of amammalian subject; and including a medicament applicator supported bythe one or more sheaths can further include a sensor configured todetect a physiological condition of the mammalian subject. The sensorcan be configured to detect one or more of movement of the contactedbody contour, tissue swelling, tissue pressure, tissue color, tissuetemperature, environmental temperature, electrical property of tissue,optical property of tissue, perspiration, or presence of an analyte.Temperature can refer to one or more of body temperature, tissuetemperature, or environmental temperature. In detailed aspects, thedevice including the one or more sheaths can contain sensors to monitorthe ambulatory movements of the patient and to actuate the applicator.The sensor can be, for example, an accelerometer, a bonded piezoelectriccrystal, a mercury switch, or a gyro that generates a signal as afunction of patient activity, e.g., body motion, footfalls or otherimpact events. One or more processors can determine an activity levelbased on a signal generated by one of these types of sensors. The one ormore processors can be configured to sample the signal and determine anumber of activity counts during the sample period. The processor canthen store the determined number of activity counts in memory of acomputing device as an activity level. The sensors can transmitinformation via the processor to a computer terminal for analysis or tothe patient, healthcare workers, or caregivers. See, e.g., U.S.2007/0250134 or U.S. 2007/0255118, each of which is incorporated hereinby reference. In detailed aspects, the device including the sensor caninclude a wearable, hip-mounted movement monitor including a triaxialaccelerometer that reports data to a microcontroller withmicro-circuitry and software to monitor and record ambulatory movementof the mammalian subject. The triaxial accelerometer can include twoorthogonally mounted dual axis accelerometers, e.g., MXR7210GL,available from MEMSIC, Inc., North Andover, Mass. The microcontrollercan sample output signals from the accelerometers, and the data can beanalyzed using a classification algorithm embedded in flash memory ofthe microcontroller, e.g., microcontroller MSP430F149, available fromTexas Instruments, Dallas, Tex. See, e.g., Karantonis, et al., IEEETrans. Info. Tech. Biomed. 10: 156-167, 2006, which is incorporatedherein by reference. The movement sensor can distinguish a number ofambulatory states. For example the movement sensor can distinguishbetween periods of activity and rest, recognize postural orientation,detect walking, or provide an estimate of metabolic energy expenditure.The movement sensor and connected microcontroller can also includeprogramming having predetermined parameters of posture, movement andmetabolic energy expenditure. Such parameters can represent thresholdsfor the microcontroller to signal the actuators, e.g., solenoids, of theapplicator. The microcontroller can instruct the actuators to deliverone or more medicaments to the one or more joint tissues of themammalian subject. Parameters of posture, movement and energyexpenditure can also be derived from historical data obtained with themovement sensor from the current patient or from previous patients. Themovement sensor and microcontroller can transmit data on movement,posture, and energy expenditure to a computing device to analyze thedata or to the patient, healthcare workers, and/or caregivers. Themovement sensor and microcontroller can further transmit data on thedosing and scheduling of medicament delivery for the patient. The sheathdevice including a medicament applicator and motion sensors can furtherinclude a power source and micro-circuitry to control the dose andschedule of the one or more medicaments delivered to the one or morejoint tissues of the mammalian subject. A power source including alithium battery can provide electric current to drive solenoid actuatorvalves and a minipump that are connected to a therapeutic medicamentreservoir and arrays of medicament applicators. In an aspect, the powersource can include a motion-activated generator, e.g., piezoelectricactuator, hydraulic power, mechanical power, or spring-activated power,wherein the power source is powered by motion of the body of themammalian subject. In further aspects, the battery can include, but isnot limited to, a thin-film electrochemical cell, a lithium ion battery,a zinc-air battery, a lithium manganese oxide battery, a zinc manganeseoxide battery, a lithium sulfuryl chloride battery, a lithium polymerbattery, a lithium vanadium oxide battery, and a nickel metal hydridebattery. See e.g., U.S. Pat. No. 5,338,625, which is incorporated hereinby reference.

In an aspect, the device including one or more sheaths configured tocontact a body contour at one or more joints of articulating bone of amammalian subject, further including one or more sensors, can generate asignal as a function of patient activity and patient posture. The devicecan further include a controller configured to respond to the sensor andto activate the applicator supported by the one or more sheaths. Forexample, the sensors can include one or more of accelerometers, gyros,or magnetometers that can generate signals that indicate both theactivity and the posture of a patient.

In an aspect, in order to identify posture, sensors such asaccelerometers can be oriented substantially orthogonally with respectto each other. In addition to being oriented orthogonally with respectto each other, each of the sensors used to detect the posture of apatient can be substantially aligned with an axis of the body of apatient. When accelerometers, for example, are aligned in this manner,the magnitude and polarity of DC components of the signals generated bythe accelerometers indicate the orientation of the patient relative tothe Earth's gravity, e.g., the posture of a patient. See e.g., U.S. Pat.No. 5,593,431; or U.S. 2007/0250134, each of which is incorporatedherein by reference.

Other sensors that can generate a signal to activate the device includesensors that include electrodes to generate a signal as a function ofelectrical activity within muscles of a patient, e.g., an electromyogram(EMG) signal, to indicate posture or activity of the patient. In anaspect, sensors can include bonded piezoelectric crystal that generatesa signal as a function of contraction of muscles. Electrodes or bondedpiezoelectric crystals can be implanted in the legs, buttocks, chest,abdomen, or back of a patient, and coupled to the device wirelessly orvia one or more leads. Alternatively, electrodes can be integrated in ahousing of the device or piezoelectric crystals can be bonded to thehousing when the sensor is implanted in the buttocks, chest, abdomen, orback of a patient. The signals generated by such sensors when implantedin these locations can vary based on the posture of a patient, e.g., canvary based on whether the patient is standing, sitting, or lying down.

In a further aspect, the posture of a patient can affect the thoracicimpedance of the patient. Sensors can include an electrode pair,including one electrode integrated within the housing of the device andone electrode in contact with an area of the patient's thorax, whereinthe sensors can generate a signal as a function of the thoracicimpedance of the patient. The controller in communication with thesensor can include a processor to detect the posture or postural changesof the patient based on the signal. The electrodes of the pair can belocated on opposite sides of the patient's thorax. For example, thedevice can include one electrode pair located proximate to the spine ofa patient for delivery of the anti-inflammatory medicament. In addition,the device with one electrode integrated in its housing and oneelectrode in the area of the patient's thorax can be implanted in theabdomen or chest of patient. In a further aspect, the device can includeelectrodes implanted to detect thoracic impedance in addition to leadsimplanted within the brain of the patient. The posture or posturalchanges can affect activation of the device for the delivery of theanti-inflammatory medicament to the patient for the treatment of aninflammatory disorder of the joints of the patient.

Additionally, changes in the posture of a patient can cause pressurechanges within the cerebrospinal fluid (CSF) of the patient.Consequently, sensors can include pressure sensors coupled to one ormore intrathecal or intracerebroventricular catheters, or pressuresensors coupled to the device wirelessly or via leads. CSF pressurechanges associated with postural changes can be particularly evidentwithin the brain of the patient, e.g., can be particularly apparent inan intracranial pressure (ICP) waveform.

In an aspect, the processor can monitor a signal that indicates aphysiological parameter of a patient, which in turn varies as a functionof patient activity. For example, the processor can monitor a signalthat indicates movement of the contacted body contour, tissue swelling,tissue pressure, tissue color, tissue temperature, environmentaltemperature, electrical property of tissue, optical property of tissue,perspiration, or presence of an analyte in the patient. In an aspect,the processor can periodically determine a measured value of one or moresensor configured to detect movement of the contacted body contour,tissue swelling tissue pressure, tissue color, tissue temperature,environmental temperature, electrical property of tissue, opticalproperty of tissue, perspiration, or presence of an analyte in thepatient based on the signal. Temperature can refer to one or more ofbody temperature, tissue temperature, or environmental temperature. Thedetermined values of these parameters can be, for example, mean ormedian values. See, e.g., U.S. Pat. No. 5,593,431; U.S. 2007/0250134,each of which are incorporated herein by reference.

In an aspect, the device can include one or more sheaths and amedicament applicator supported by the one or more sheaths configured toinject one or more medicaments to one or more joint tissues, wherein thedevice includes a pharmaceutical composition including the one or moremedicaments in a thixotropic medium. The pharmaceutical compositionincluding the one or more medicaments in a thixotropic medium promotesdelivery of high concentrations of the one or more medicaments to theone or more joint tissues. Thixotropic media, e.g., α-cyclodextrin andcarteolol hydrochloride, are useful for pharmaceutical applicationsbecause thixotropic pharmaceutical compositions display reducedviscosity when subjected to shear stress such as high velocity flowthrough the applicator, e.g., a microjet applicator. See, e.g., U.S.Pat. No. 6,143,329 entitled “Aqueous-based pharmaceutical composition”issued to Kim on Nov. 7, 2000, which is incorporated herein byreference. For example, parenteral injection of a thixotropic suspensionof a pharmaceutical mixed with a small amount of polysorbate 80(Mallincrodt Baker, Inc., Phillipsburg, N.J.) in water is decomposed toa liquid during passage through a medicament applicator, but regains ahydrogel structure and forms cohesive depots in the body. See Lee etal., J. Contr. Rel. 136: 88-98, 2009, which is incorporated herein byreference. Semisolid formulations comprised of solid lipid nanoparticlesloaded with pharmaceuticals and Carbopol® 934 poly(acrylic acid)microgel have thixotropic properties. See Lee et al., Ibid. Aparticulate thixotropic medium combined with an anti-inflammatorymedicament and co-delivered at high velocity to one or more jointtissues of the mammalian subject can achieve increased penetration ofone or more of epidermal tissue, fibrous capsule, subsynovial tissue orsynovial membrane. Moreover, the properties of the pharmaceuticalformulation including thixotropic medium can lead to formation anddeposition of the anti-inflammatory medicament as a viscous liquid orhydrogel solution in the one or more joint tissues and in the jointsynovial cavity of the mammalian subject.

A system is described that includes an apparatus including a sensorconfigured to detect one or more physiological conditions of one or morejoints of articulating bone of a mammalian subject, and a controllerconfigured to communicate with the sensor. The controller can beconfigured to activate the device including one or more sheathsconfigured to contact one or more body contours in proximity to one ormore joints of articulating bone of the mammalian subject. The devicecan further include one or more microjet applicators supported by theone or more sheaths and configured to inject one or more medicaments toone or more joint tissues of the mammalian subject.

A method is described that includes injecting one or more medicaments toone or more joint tissues of a mammalian subject, wherein the injectingof the one or more medicaments is by a device that includes one or moresheaths configured to contact one or more body contours in proximity toone or more joints of articulating bone of the mammalian subject, andone or more microjet applicators supported by the one or more sheathsand configured to inject one or more medicaments to one or more jointtissues of the mammalian subject.

A method is described that includes producing a device configured toinject one or more medicaments to one or more joint tissues of amammalian subject, wherein the device includes one or more sheathsconfigured to contact one or more body contours in proximity to one ormore joints of articulating bone of the mammalian subject, and one ormore microjet applicators supported by the one or more sheaths andconfigured to inject one or more medicaments to one or more jointtissues of the mammalian subject. The applicator can include, but is notlimited to, one or more high speed microjets, one or more microneedles,one or more microfine lances, one or more microfine cannulas, one ormore microprojections, or one or more electrodes. The one or moresheaths can be configured to contact the one or more body contours inproximity to the one or more joints of the mammalian subject. The methodcan further include providing a sensor configured to detect aphysiological condition of the mammalian subject. The sensor can beconfigured to detect movement of the contacted body contour, tissueswelling, tissue pressure, tissue color, tissue temperature,environmental temperature, electrical property of tissue, opticalproperty of tissue, perspiration, or presence of an analyte. Temperaturecan refer to one or more of body temperature, tissue temperature, orenvironmental temperature. The method can further include providing acontroller configured to respond to the sensor, the controllerconfigured to control release of the one or more medicaments from theapplicator. The controller can be configured to control a timed releaseof the one or more medicaments. The sensor can be configured to monitorjoint movement, body movement, or gait of the mammalian subject. Thesensor can be configured to monitor posture of the mammalian subject Theapplicator can be configured to respond to the sensor detecting movementof the contacted body contours, wherein the one or more applicators areconfigured to inject the one or more medicaments into the one or morejoint tissues of the mammalian subject.

A device is described that includes an enclosure including one or moresensors, a controller, and one or more applicators configured tosurround one or more joints of articulating bone of a mammalian subject.The one or more sensors are distributed within the enclosure and areconfigured to detect one or more physiological conditions of one or morejoints as they are placed within the enclosure by the mammalian subject.The controller can be configured to communicate with the sensor, whereinthe controller is configured to activate the one or more applicatorssupported by one or more substrates configured to contact one or morebody contours in proximity to the one or more joints of the mammaliansubject. The controller in combination with the sensor can be configuredto position the one or more applicators to locate the applicators nearthe one or more joints. When the one or more applicators are locatednear the one or more joints, the one or more applicators are configuredto inject one or more medicaments to the one or more joint tissues ofthe mammalian subject. In an aspect, the sensor can be configured todetect the one or more physiological conditions of the one or morejoints by ultrasonic imaging of the one or more joints. A liquid can beconfigured between an ultrasonic transducer and the one or more jointsfor the ultrasonic imaging of the one or more joints of the mammaliansubject. In a further aspect, the one or more sensors can be configuredto detect the one or more physiological conditions of the one or morejoints by X-ray imaging of the one or more joints. In a further aspect,the one or more joints can include, for example, one or more of handjoints, wrist joints, elbow joints, or shoulder joints; or one or moreof foot joints, ankle joints, knee joints, or hip joints.

In an aspect, the one or more medicaments can include, but is notlimited to, steroids, corticosteroids, analgesics, anti-inflammatories,or NSAIDs. The device can deliver the one or more medicaments to the oneor more joints of the mammalian subject compared to systemic delivery ofthe one or more medicaments. NSAIDs can include, but are not limited to,acemetacin, amtolmetin, azapropazone, benorilate, benoxaprofen,benzydamine hydrochloride, bromfenal, bufexamac, butibufen, carprofen,celecoxib, choline salicylate, dipyone, droxicam, etodolac, etofenamate,etoricoxib, felbinac, fentiazac, floctafenine, indoprofen, isoxicam,lomoxicam, loxoprofen, licofelone, fepradinol, magnesium salicylate,meclofenamic acid, meloxicam, morniflumate, niflumic acid, nimesulide,oxaprozen, piketoprofen, priazolac, pirprofen, propyphenazone,proquazone, rofecoxib, salalate, sodium salicylate, sodiumthiosalicylate, suprofen, tenidap, tiaprofenic acid, trolaminesalicylate, or zomepirac. The NSAID can further include, but is notlimited to, aclofenac, aloxiprin, naproxen, aproxen, aspirin, diclofenacsodium, diflunisal, fenoprofen, indomethacin, mefenamic acid, piroxicam,phenylbutazone, salicylamide, salicylic acid, sulindac, desoxysulindac,tenoxicam, tramadol, ketoralac, clonixin, fenbufen, benzydaminehydrochloride, meclofenamic acid, flufenamic acid, or tolmetin. See,e.g., U.S. Pat. No. 7,387,789, U.S. Pat. No. 6,818,226, or U.S. Pat. No.5,374,661, each of which is incorporated herein by reference. The NSAIDcan further include, but is not limited to, choline magnesiumtrisalicylate (Trilisate®), diflunisal (Dolobid®), fenoprofen (Nalfon®),flurbiprofen (Ansaid®), ketoprofen (Orudis®, Actron®, or Oruvail®),nabumetone (Relafen®), or salsalate (Salflex®, Disalcid®, or Amigesic®).Anti-inflammatory agents, include, but are not limited to, betamethasone21-phosphate disodium salt, triamcinolone acetonide 21 disodiumphosphate, hydrocortamate hydrochloride, hydrocortisone 21-phosphatedisodium salt, methylprednisolone 21-phosphate disodium salt,methylprednisolone 21-succinaate sodium salt, paramethasone disodiumphosphate and prednisolone 21-succinate sodium salt, and anticoagulants,such as citric acid, citrate salts (e.g., sodium citrate), dextrinsulfate sodium, and EDTA. See, e.g., U.S. 2006/0036209, which isincorporated herein by reference.

One or more therapeutic medicaments, alone or in combination with otherdrugs or agents, formulated for delivery to a tissue of one or morejoints of a mammalian subject, can be prepared as pharmaceuticalcompositions that contain one or more added materials such as carriers,vehicles, and/or excipients. “Carriers,” “vehicles” and “excipients”generally refer to substantially inert materials that are nontoxic anddo not interact with other components of the composition in adeleterious manner. Exemplary carriers, vehicles, or excipients can befound, e.g., in the U.S. Food and Drug Administration inactiveingredients database athttp://www.fda.gov/Drugs/InformationOnDrugs/ucm080123.htm. Examples ofsuitable carriers include, but are not limited to, water, silicone,gelatin, or waxes. Examples of normally employed “excipients,” include,but are not limited to, pharmaceutical grades of dextrose, sucrose,lactose, trehalose, mannitol, sorbitol, inositol, dextran, starch,cellulose, sodium or calcium phosphates, calcium sulfate, citric acid,tartaric acid, glycine, or high molecular weight polyethylene glycols(PEG), or combinations thereof. In addition, it may be desirable toinclude a charged lipid and/or detergent in the pharmaceuticalcompositions. Such materials can be used as stabilizers oranti-oxidants, or used to reduce the possibility of local irritation atthe site of administration. Suitable charged lipids include, but are notlimited to, phosphatidylcholines (lecithin). Detergents will typicallybe a nonionic, anionic, cationic or amphoteric surfactant. Examples ofsuitable surfactants include, for example, Tergitol® and Triton®surfactants (Union Carbide Chemicals and Plastics, Danbury, Conn.),polyoxyethylenesorbitans, e.g., TWEEN® surfactants (Atlas ChemicalIndustries, Wilmington, Del.), polyoxyethylene ethers, e.g., Brij,pharmaceutically acceptable fatty acid esters, e.g., lauryl sulfate andsalts thereof (SDS).

With reference to the figures, and with reference now to FIGS. 1 and 2depicted is an aspect of a device or method that can serve as anillustrative environment of and/or for subject matter technologies, forexample, a device including one or more sheaths configured to contact abody contour at one or more joints of articulating bone of a mammaliansubject; and an applicator supported by the one or more sheaths andconfigured to inject one or more medicaments to a tissue of the one ormore joints of the mammalian subject.

FIG. 1 depicts a diagrammatic view of an aspect of a device 100. Thedevice 100 includes one or more sheaths 110 configured to contact a hand160 at one or more joints of articulating bone in the hand of amammalian subject, and an applicator 120, e.g., one or more of highspeed microjets, microneedles, microfine lances, microfine cannulas,microprojections, or electrodes, supported by the one or more sheaths110 and configured to inject one or more medicaments to a tissue of theone or more joints of the mammalian subject. The device can furtherinclude a sensor 130 configured to detect a physiological condition ofthe mammalian subject such as, for example, a sensor to detect movementof the contacted body contour, a sensor to detect tissue swelling,tissue pressure, or tissue color, a sensor to detect tissue temperature,environmental temperature, a sensor to detect electrical property oftissue, optical property of tissue, or perspiration, or a sensor todetect presence of an analyte. The device can further include acontroller 140 in communication with the sensor 130 and the fluiddisplacement actuator 125. The controller is configured to activate thefluid displacement actuator 125 and the applicator 120 utilizing acomponent 150 for transient mechanical/electrical acceleration of theone or more medicaments from the applicator 120.

FIG. 2 depicts a diagrammatic view of an aspect of a device 200. Thedevice 200 includes one or more sheaths 210 configured to contact a legand knee 260 at one or more joints of articulating bone in the hand of amammalian subject, and an applicator 220, e.g., one or more of highspeed microjets, microneedles, microfine lances, microfine cannulas,microprojections, or electrodes, supported by the one or more sheaths210 and configured to inject one or more medicaments to a tissue of theone or more joints of the mammalian subject. The device can furtherinclude a sensor 230 configured to detect a physiological condition ofthe mammalian subject. The device can further include a controller 240in communication with the sensor 230 and the fluid displacement actuator225. The controller is configured to activate the fluid displacementactuator 225 and the applicator 220 utilizing a component 250 fortransient mechanical/electrical acceleration of the one or moremedicaments from the applicator 220.

FIG. 3 illustrates an exemplary aspect of a knee joint. The knee jointis the junction of three bones: the femur 360, the tibia 370, and thepatella 320. The patella is 2 to 3 inches wide and 3 to 4 inches long.It protects the knee and gives leverage to muscles. The ends of thethree bones in the knee joint are covered with articular cartilage 330that helps absorb shock and allows the knee joint to move smoothly.Separating the bones of the knee are two crescent-shaped discs ofconnective tissue called menisci 340. The menisci 340 are positionedbetween the tibia 370 and femur 360 on the outer and inner sides of eachknee. The two menisci in each knee act as shock absorbers, cushioningthe lower part of the leg from the weight of the rest of the body aswell as enhancing stability. The quadriceps tendon 310 connects thequadriceps muscle to the patella and provides the power to straightenthe knee. The patellar tendon 310 connects the tibia to the patella.Four ligaments connect the femur and tibia and give the joint strengthand stability. The medial collateral ligament (MCL) 350, which runsalong the inside of the knee joint, provides stability to the medialpart of the knee. The lateral collateral ligament (LCL) 350, which runsalong the outside of the knee joint, provides stability to the lateralpart of the knee. The anterior cruciate ligament (ACL) 350, in thecenter of the knee, limits rotation and the forward movement of thetibia. The posterior cruciate ligament (PCL) 350, also in the center ofthe knee, limits backward movement of the tibia. The knee capsule is aprotective, fiber-like structure that wraps around the knee joint.Inside the capsule, the joint is lined with a thin, soft tissue calledsynovium.

FIG. 4 illustrates an exemplary method including injecting one or moremedicaments to one or more joint tissues of a mammalian subject. Themethod 400 comprises injecting 401 one or more medicaments to one ormore joint tissues of a mammalian subject, wherein the injecting of theone or more medicaments is via a device 402 including one or moresheaths configured to contact one or more body contours in proximity toone or more joints of articulating bone of the mammalian subject; andone or more microjet applicators supported by the one or more sheathsand configured to inject one or more medicaments to one or more jointtissues of the mammalian subject. The method can further includeproviding one or more sensors 403 configured to detect a physiologicalcondition of the mammalian subject. The method can further includeproviding one or more sensors 404 configured to determine quality oflocation or quality of contact placement of the one or more sheaths onthe one or more body contours. The method can further include providinga controller 405 configured to control release of the one or moremedicaments from the one or more applicators. In an aspect, the one ormore applicators 406 includes one or more high speed microjets, one ormore microneedles, one or more microfine lances, one or more microfinecannulas, one or more microprojections, or one or more electrodes. In afurther aspect, the one or more sensors 407 are configured to detect oneor more conditions at one or more of the one or more joints and thecontroller is configured to control release of the one or moremedicaments at others of the one or more joints of the mammaliansubject. In a further aspect, the one or more sheaths 408 can include asleeve-shaped article of clothing or a sleeve-shaped body covering.

The methods and compositions are further described with reference to thefollowing examples; however, it is to be understood that the methods andcompositions are not limited to such examples.

EXAMPLES Example 1 A Knee Brace Device with Embedded Microjets andPiezoelectric Actuators Configured to Deliver Naproxen (e.g., Naprosyn®)to an Arthritic Knee at High Local Concentrations in a Time DependentManner

A device is provided to treat a patient with an arthritic knee. Thedevice is a knee brace that is worn on the knee and delivers high localconcentrations of an anti-inflammatory drug to the knee joint usingmicrojets that are driven by piezoelectric actuators. The patient whohas chronic pain and stiffness in a knee joint is clinically diagnosedto have moderate osteoarthritis as confirmed by radiography. To reducepain and stiffness, a knee brace device is wrapped to contact theaffected knee and positioned to substantially align multiple embeddedmicrojets with one or more of the superior, inferior, lateral, medial,posterior or anterior aspects of the knee joint. The multiple embeddedmicrojets are configured to provide transdermal delivery of highlyconcentrated therapeutic medicaments localized to the knee joint and mayeffectively deliver the therapeutic medicaments to tissues of the kneejoint without risk of adverse reactions associated with oral systemicmedicament. The device can deliver highly concentrated therapeuticmedicaments to tissues of the knee joint including one or more of afibrous capsule, subsynovium, synovial membrane, synovium, joint cavity,synovial fluid, articular cartilage, subchondral bone, or ligament. Theknee brace device is held in place by velcro strips and alignment of themicrojets to the synovial joint is referenced to the knee cap and to anopening in the knee brace. Alternatively, the knee brace device may bean elastic sleeve with embedded microjets aligned to the knee joint byvisual inspection when it is slipped over the knee. The microjets areconnected to a reservoir containing naproxen (Naprosyn®, available fromRoche Laboratories, Nutley, N.J.) to provide anti-inflammatorymedicament for repeated local delivery to the knee joint. Local deliveryof concentrated naproxen solutions (e.g., approximately 25-200 mg/ml)may be achieved while avoiding potential adverse reactions. For example,a single microjet activated with a piezoelectric crystal maytransdermally deliver approximately 28 mg of a drug in a day from areservoir with a 20 mg/ml solution of drug. See, e.g., Arora et al.,Proc. Natl. Acad. Sci. USA, 104: 4255-4260, 2007, which is incorporatedherein by reference. Localized dosing of a concentrated naproxensuspension (e.g., Naprosyn® suspension 25 mg/ml, available from RocheLaboratories, Nutley, N.J.) at the knee joint may be accomplished with aknee brace device containing multiple embedded microjets actuated bypiezoelectric actuators that are controlled electronically using alithium battery as a source of power. Piezoelectric crystal actuatorsexpand when electronically activated to drive small liquid volumes(e.g., 10-15 nanoliters) through a microjet at high velocity (greaterthan 100 meter/sec). The high velocity (ν>100 m/s) of microjets allowstheir entry into the skin, whereas the small jet diameters (50-100 μm)and extremely small volumes (2-15 nanoliters) limit the penetrationdepth (˜200 μm) See, e.g., U.S. 2008/0091139 entitled “Methods, Devicesand Kits for Microjet Drug Delivery” published Apr. 17, 2008; and Aroraet al., Ibid. The rate of drug delivery may be modulated by varying theelectronic signal frequency. For example, electronic signals topiezoelectronic crystals at 10 Hz actuate microjets ten times fasterthan 1 Hz signals and increase the rate of drug delivery by ten-fold.See, e.g., Arora et al., Ibid. In addition, the dosing of naproxen mayalso be controlled by variation of the drug concentration in thereservoir. Drug solutions or suspensions may be approximately 2 mg/ml,up to approximately 20 mg/ml, or up to approximately 200 mg/ml.

The knee brace device may be worn throughout the day and activated asneeded by the patient via an electronic switch that controls thepiezoelectric actuators driving multiple microjets. For example anelectronic switch on the knee brace device may be turned on voluntarilyby the patient “as needed” in response to pain and stiffness.Micro-circuitry, including a timer in the knee brace device maydetermine the duration of drug delivery (and therefore dose) followingactivation of the device. Alternatively, the knee brace device withmicro-circuitry may be programmed to periodically deliver naproxentransdermally throughout the day and night on a predetermined dose andschedule as determined by the patient or the patient's physician with noneed for manual activation.

Example 2 A Device Including a Sheath Bandage Containing EmbeddedMicroneedles to Deliver Diclofenac Sodium (e.g., Voltaren®) at HighLocal Concentration to Joint Tissue in a Time Dependent Manner to Treata Patient with Osteoarthritis in a Wrist Joint

A device is provided to treat a patient with osteoarthritis of thewrist. The device is a sheath bandage that is worn on the wrist anddelivers high local concentrations of an anti-inflammatory drug to thewrist joint using microneedles that deliver drugs at high concentrationsthrough the skin to wrist joint tissues and to the synovial cavity. Thepatient who has chronic pain and stiffness in a wrist joint isclinically diagnosed to have moderate osteoarthritis as confirmed byradiography. To reduce pain and stiffness a wrist sheath bandage deviceis applied to contact the affected wrist and positioned to alignmultiple embedded microneedles with the wrist joint. The multipleembedded microneedles are configured to provide transdermal delivery ofhighly concentrated therapeutic medicaments localized to the wrist jointand may effectively deliver the therapeutic medicaments to tissues ofthe wrist joint including one or more of a fibrous capsule, subsynovium,synovial membrane, synovium, joint cavity, synovial fluid, articularcartilage, subchondral bone, and/or ligaments without risk of adversereactions associated with oral systemic medicaments.

The wrist sheath bandage device is held in place by adhesive strips andalignment of the microneedles to the wrist joint is referenced topalpable projections of the pelvic bone, specifically, the anteriorsuperior iliac spine, and of the femur, specifically, the greatertrochanter. The wrist sheath bandage device may alternatively be anelastic band with embedded microneedles aligned to the wrist joint byvisual inspection. The wrist sheath bandage device may also have atourniquet to apply a constricting force and/or pressure on themicroneedles to insure penetration of the stratum corneum. Apressure-exerting element for applying pressure to an elastic body isdescribed in Gavriely, et al., U.S. 2009/0155341 A1 entitled “MedicalDevice and A Method for Applying A Biochemically Active Material On Oneor More Body Parts” published Jun. 18, 2009 which is incorporated hereinby reference. The wrist sheath bandage device may further apply pressureon the microneedles to insure penetration of the microneedles directlyinto the one or more joint tissues including one or more of a fibrouscapsule, subsynovium, synovial membrane, synovium, joint cavity,synovial fluid, articular cartilage, subchondral bone, and/or ligaments.The microneedles are connected to a reservoir containing diclofenac(Voltaren®, available from Novartis Pharmaceuticals Corp., East Hanover,N.J.) to provide an anti-inflammatory and analgesic medicament forrepeated local delivery to the wrist joint. Local delivery ofconcentrated diclofenac solutions, e.g., 200 mg/ml, may be achievedwhile maintaining low plasma concentrations and avoiding potentialadverse reactions observed with oral administration. An oral dose of 75mg diclofenac sodium results in a mean peak plasma concentration equalto 1.9 μg/ml, while topical diclofenac sodium (Pennsaid® available fromNuvo Research Inc., Mississauga, Ontario, Canada) reaches a mean peakplasma concentration of 11.8±4.2 ng/ml. See Ozguney, Expert Opin.Pharmacother., 9: 1805-1816, 2008, which is incorporated herein byreference.

The wrist sheath bandage device contains a medicament applicatorcomprised of hollow microneedle arrays that are connected to a reservoircontaining medicaments. Hollow microneedle arrays may be fabricatedusing microfabrication technology adapted from the microelectronicsindustry. For example silicon hollow microneedle arrays may befabricated by etching holes through silicon wafers using deep reactiveion etching and then etching microneedles around the holes. See, e.g.,McAllister et al., Proc. Natl. Acad. Sci. USA, 100: 13755-13760, 2003,which is incorporated herein by reference. Microneedle arrays (10×10)containing approximately 100 to approximately 400 microneedles in anarea of 3 mm×3 mm are constructed with conical microneedlesapproximately 150 μm in length; with a base diameter of approximately 80μm and a tip with approximately a 1 μm radius of curvature. Hollowmicroneedles with diameters between 35 μm and 300 μm and lengths between150 μm and 1000 μm may be fabricated as shown by McAllister et al.,Ibid. Alternatively hollow microneedles may be fabricated from metals,e.g., Ni or NiFe, or polymers, e.g., polyglycolic acid and poly lacticacid, by using micromolds or by electroplating polymer microneedles withnickel as shown by McAllister et al., Ibid. Hollow microneedle arraysmay be connected via a manifold to a mini-pump, solenoid valve actuatorsand to a reservoir containing medicaments. Mini-pumps and solenoidvalves are available from Parker-Hannifin, Precision Fluidics Division,Hollis, N.H. The applicator, comprised of hollow microneedle arrays,solenoid valve actuators, a minipump and a reservoir is embedded in thewrist sheath bandage device with the hollow microneedles facing thestratum corneum overlaying the wrist joint. Multiple medicamentapplicator units may be supported by the wrist sheath bandage device toalign with different aspects of the wrist joint, e.g., anterior,posterior, lateral, medial, superior, inferior.

The wrist sheath bandage device with a medicament applicator has a powersource and micro-circuitry to control the dose and schedule ofdiclofenac sodium delivered to the wrist joint. A lithium battery mayprovide electric current to drive solenoid actuator valves and aminipump which are connected to a medicament reservoir and microneedlearrays. The wrist sheath bandage device may apply pressure on themicroneedles to insure penetration of the stratum corneum, epidermis, ordermis. The wrist sheath bandage device may further apply pressure onthe microneedles to insure penetration of the microneedles directly intothe one or more joint tissues including one or more of a fibrouscapsule, subsynovium, synovial membrane, synovium, joint cavity,synovial fluid, articular cartilage, subchondral bone, and/or ligaments.Delivery of diclofenac may be manually controlled by flipping a switchwhich provides electric current to the applicator. This may be done “asneeded” for pain and stiffness. The dose of diclofenac sodium deliveredmay be determined by the concentration of diclofenac in the reservoirand the duration of the electric current. Micro-circuitry may monitorthe total dose of diclofenac delivered within 24 hours and control drugdelivery to prevent exceeding the maximum recommended dose. The wristsheath bandage device may also have micro-circuitry including a timerthat allows the patient, or a healthcare worker to program a dose andschedule of diclofenac sodium delivery. The dosing schedule may spanhours, days, weeks or months and the micro-circuitry can record andstore total dosage and/or dosage within a fixed time period of hours,days, weeks or months. The wrist sheath bandage device may transmitinformation including drug dosage, schedule, and drug consumption to acomputer network system that includes the patient, the patient's family,healthcare providers, insurance companies, regulatory authorities andpublic health officials.

Example 3 A Sheath Device with Microneedle Arrays and Sensors to MonitorMovement and Deliver Naproxen (e.g., Naprosyn®) to the Hip Joint of aPatient with Osteoarthritis

A device is provided to treat a patient with osteoarthritis of the hip.The device includes one or more sheaths that is worn on the hip anddelivers high local concentrations of an anti-inflammatory drug to thehip joint using microneedles that deliver drugs at high concentrationsthrough the skin to hip joint tissues and to the synovial cavity. Thedevice also contains sensors to monitor the gait of the patient and tosignal the applicator to deliver an anti-inflammatory, naproxen. Thepatient who has chronic pain and stiffness in a hip joint is clinicallydiagnosed to have moderate osteoarthritis as confirmed by radiography.To reduce pain and stiffness and to improve mobility a hip sheath deviceis applied to contact the affected hip and positioned to align multipleembedded microneedles with the hip joint as well as sensors to monitorthe patient's gait. The multiple embedded microneedles are configured toprovide transdermal delivery of highly concentrated therapeuticmedicaments localized to the hip joint and may effectively deliver thetherapeutic medicaments to tissues of the hip joint including one ormore of a fibrous capsule, subsynovium, synovial membrane, synovium,joint cavity, synovial fluid, articular cartilage, subchondral bone,and/or ligaments. The device delivers the highly concentratedtherapeutic medicaments localized to the hip joint without risk ofadverse reactions associated with oral systemic medicaments.

The hip sheath device is slipped over the hip and alignment of themicroneedles to the hip joint is referenced to palpable projections ofthe pelvic bone, specifically, the anterior superior iliac spine, and ofthe femur, specifically, the greater trochanter. The hip sheath devicealso has sensors to monitor the arthritic patient's gait. A sensor tomonitor gait is described by Miesel et al., U.S. 2007/0250134 A1entitled “Collecting Gait Information for Evaluation and Control ofTherapy” published Oct. 25, 2007 which is incorporated herein byreference. The hip sheath device may also have a tourniquet to apply aconstricting force and/or pressure on the microneedles to insurepenetration of the stratum corneum. The hip sheath device may furtherapply pressure on the microneedles to insure penetration of themicroneedles directly into the one or more joint tissues including oneor more of a fibrous capsule, subsynovium, synovial membrane, synovium,joint cavity, synovial fluid, articular cartilage, subchondral bone,and/or ligaments. A pressure-exerting element for applying pressure toan elastic body is described in Gavriely, et al., U.S. 2009/0155341 A1entitled “Medical Device and A Method for Applying A BiochemicallyActive Material On One or More Body Parts” published Jun. 18, 2009 whichis incorporated herein by reference. The microneedles are connected to areservoir containing naproxen (Naprosyn®, available from RocheLaboratories, Nutley, N.J.) to provide anti-inflammatory medicament forrepeated local delivery to the knee joint. Local delivery ofconcentrated naproxen solutions, e.g., approximately 25-200 mg/ml, maybe achieved while avoiding potential adverse reactions. Elimination ofnaproxen from synovial fluid is slow, and appreciable drugconcentrations may still be measurable after 24 hours. During once dailydosing of naproxen sodium, naproxen should accumulate in synovial fluid,a steady-state being achieved within a week of treatment. The predictedaccumulation ratio based on trough concentration is 2.4. See, e.g.,Bruno et al., Br. J. clin. Pharmac., 26: 41-44, 1988, which isincorporated herein by reference.

The hip sheath device contains a medicament applicator comprised ofhollow microneedle arrays that are connected to a reservoir containingtherapeutic medicaments. Hollow microneedle arrays may be fabricatedusing microfabrication technology adapted from the microelectronicsindustry. For example silicon hollow microneedle arrays may befabricated by etching holes through silicon wafers using deep reactiveion etching and then etching microneedles around the holes. See, e.g.,McAllister et al., Proc. Natl. Acad. Sci. USA, 100: 13755-13760, 2003which is incorporated herein by reference. Microneedle arrays (10×10)containing 100 microneedles in an area of 3×3 mm are constructed withconical microneedles approximately 150 μm in length; with a basediameter of approximately 80 μm and a tip with approximately a 1 μmradius of curvature. Hollow microneedles with diameters between 35 μmand 300 μm and lengths between 150 μm and 1000 μm may be fabricated asshown by McAllister et al., Ibid. Alternatively hollow microneedles maybe fabricated from metals, e.g., Ni or NiFe, or polymers, e.g.,polyglycolic acid and poly lactic acid, by using micromolds or byelectroplating polymer microneedles with nickel as shown by McAllisteret al., Ibid. Hollow microneedle arrays may be connected via a manifoldto a mini-pump, solenoid valve actuators and to a reservoir containingmedicaments. Mini-pumps and solenoid valves are available fromParker-Hannifin, Precision Fluidics Division, Hollis, N.H. Theapplicator comprised of hollow microneedle arrays, solenoid valveactuators, a minipump and a reservoir is embedded in the hip sheathbandage device with the hollow microneedles facing the stratum corneumoverlaying the hip joint. Multiple medicament microneedle arrays may besupported by the hip bandage device to align with different aspects ofthe hip joint, e.g., anterior, posterior, lateral, medial, superior,inferior.

A hip sheath device may contain sensors to monitor the ambulatorymovements of the patient and to actuate the applicator. The sensors maytransmit information to the patient, healthcare workers and caregivers.For example, a wearable, hip-mounted movement monitor may be comprisedof a triaxial accelerometer and a microcontroller with micro-circuitryand software as shown by Karantonis, et al., IEEE Trans. Info. Tech.Biomed. 10: 156-167, 2006 which is incorporated herein by reference. Thetriaxial accelerometer may be comprised of two orthogonally mounted dualaxis accelerometers, e.g., MXR7210GL, available from MEMSIC, Inc., NorthAndover, Mass. A microcontroller, e.g., MSP430F149 available from TexasInstruments, Dallas, Tex., samples output signals from theaccelerometers and the data are subject to a classification algorithmembedded in flash memory of the microcontroller. See Karantonis et al.,Ibid. for details of the microcontroller and the movement classificationalgorithm. A movement sensor may distinguish between periods of activityand rest, recognize postural orientation, detect walking and provide anestimate of metabolic energy expenditure. The movement sensor andconnected microcontroller may also include predetermined parameters ofposture, movement and metabolic energy expenditure that representthresholds for signaling to actuators, e.g., solenoids, of theapplicator to deliver naproxen to the hip joint of the patient.Parameters of posture, movement and energy expenditure may be derivedfrom historical data obtained with the movement sensor from the currentpatient or from previous patients. The movement sensor andmicrocontroller may transmit data on movement, posture, and energyexpenditure to the patient, healthcare workers, and caregivers as wellas data on the dosing and scheduling of naproxen delivery.

The hip sheath device with a medicament applicator and motion sensorshas a power source and micro-circuitry to control the dose and scheduleof naproxen delivered to the hip joint. A lithium battery may provideelectric current to drive solenoid actuator valves and a minipump whichare connected to a therapeutic medicament reservoir and microneedlearrays. Delivery of naproxen may be manually controlled by flipping aswitch which provides electric current to the applicator. This may bedone “as needed” for pain and stiffness. The dose of naproxen deliveredmay be determined by the concentration of naproxen in the reservoir andthe duration of the electric current. Micro-circuitry may monitor thetotal dose of naproxen delivered within 24 hours and control drugdelivery to prevent exceeding the maximum recommended dose. The hipsheath device may also have micro-circuitry including a timer thatallows the patient or a healthcare worker to program a dose and scheduleof naproxen delivery. The dosing schedule may span hours, days, weeks,or months. The micro-circuitry can record and store total dosage and/ordosage within a fixed time period of hours, days, weeks, or months. Thehip sheath device may transmit information including drug dosage,schedule, and drug consumption to a computer network system that isaccessible by the patient, the patient's family, healthcare providers,insurance companies, regulatory authorities and/or public healthofficials.

Example 4 A Glove Device Comprised of High Speed Microjet ApplicatorsDelivers Naproxen (Naprosyn®) in a Thixotropic Medium into the Hand andWrist Joints of a Patient with Osteoarthritis

A device is provided to treat a patient with an arthritic hand andwrist. The device is a glove that is worn on the hand and delivers highlocal concentrations of an anti-inflammatory drug to the hand and wristusing microjets that are driven by piezoelectric actuators. The patientwho has chronic pain and stiffness in his hand and wrist joints isclinically diagnosed to have moderate osteoarthritis as confirmed byradiography. To reduce pain and stiffness a glove device is worn tocontact the affected hand and wrist and designed to substantially alignmultiple embedded microjets with the contours and joints of the hand andwrist. The multiple embedded microjets are configured to providetransdermal delivery of highly concentrated therapeutic medicamentslocalized to the hand and wrist joints and may effectively deliver thetherapeutic medicaments to tissues of the hand and wrist jointsincluding one or more of a fibrous capsule, subsynovium, synovialmembrane, synovium, joint cavity, synovial fluid, articular cartilage,subchondral bone, or ligament without risk of adverse reactionsassociated with oral systemic medicament. Glove devices are designed tofit right hands or alternatively left hands in sizes ranging from smallto large. For example, hands may range between approximately 154.51mm-214.9 mm in length, and 71.62 mm-119.06 mm in breadth. See Mandahawiet al., Int. J. Indust. Ergon. 38: 966-976, 2008, which is incorporatedherein by reference. A glove device substantially aligns the microjetsto deliver naproxen to one or to multiple joints of the hand and wristincluding the interphalangial articulations, metacarpophalangeal joints,intercarpal articulations and the radiocarpal joint. For additionaldetail see Gray, Gray's Anatomy: The Anatomical Basis of Medicine andSurgery, (38th ed., Churchill Livingstone 1995; ISBN: 0443045607). Themicrojets are connected to a reservoir containing naproxen (Naprosyn®,available from Roche Laboratories, Nutley, N.J.) to provideanti-inflammatory medicament for repeated local delivery to the hand andwrist joints. Local delivery of concentrated naproxen solutions (e.g.,approximately 25-200 mg/ml) may be achieved while avoiding potentialadverse reactions. Potential adverse reactions associated with systemicoral naproxen include one or more of gastrointestinal bleeding,gastrointestinal ulceration/perforation, myocardial infarction, stroke,thromboembolism, congestive heart failure, renal papillary necrosis,nephrotoxicity, or hepatotoxicity. See Physician's Desk Reference,63^(rd) ed. Thomson Healthcare, Montvale, N.J., 2009; ISSN: 0093-4461,which is incorporated herein by reference. For example, a singlemicrojet activated with a piezoelectric crystal may transdermallydeliver approximately 28 mg of a drug in a day from a reservoir with a20 mg/ml solution of drug. See, e.g., Arora et al., Proc. Natl. Acad.Sci. USA, 104: 4255-4260, 2007, which is incorporated herein byreference. Localized dosing of a concentrated naproxen suspension, e.g.,Naprosyn® suspension, 25 mg/ml, (available from Roche Laboratories,Nutley, N.J.) at hand joints and wrist joints may be accomplished with aglove device containing multiple embedded microjets actuated bypiezoelectric actuators that are controlled electronically using alithium battery as a source of power. Piezoelectric crystal actuatorsexpand when electronically activated to drive small liquid volumes,e.g., 10-15 nanoliters, through a microjet at high velocity, e.g.,greater than 100 meter/sec. See, e.g., U.S. 20080091139 entitled,“Methods, Devices and Kits for Microjet Drug Delivery” published Apr.17, 2008; and Arora et al., Ibid. The rate of drug delivery may bemodulated by varying the electronic signal frequency. For example,electronic signals to piezoelectronic crystals at 10 Hz actuatemicrojets ten times faster than 1 Hz signals and increase the rate ofdrug delivery by ten-fold. See, e.g., Arora et al., Ibid. In addition,the dosing of naproxen may also be controlled by variation of the drugconcentration in the reservoir. Drug solutions or suspensions may beapproximately 2 mg/ml, up to approximately 20 mg/ml, or up toapproximately 200 mg/ml.

A glove device with an applicator comprised of microjets to delivernaproxen at high concentration into joints of the hand and wrist maycontain naproxen in combination with a thixotropic medium which promotesdelivery of naproxen to joint tissues and the synovial cavity.Thixotropic media, e.g., alpha-cyclodextrin, carteolol hydrochloride,are useful for pharmaceutical applications because thixotropicpharmaceutical compositions display reduced viscosity when subjected toshear stress such as high velocity flow through a microjet. The use ofthixotropic media for delivery of pharmaceuticals is described in U.S.Pat. No. 6,143,329 entitled “Aqueous-based pharmaceutical composition”issued to Kim on Nov. 7, 2000, which is incorporated herein byreference. For example, parenteral injection of a thixotropic suspensionof a pharmaceutical mixed with a small amount of polysorbate 80(available from Mallincrodt Baker, Inc., Phillipsburg, N.J.) in water isdecomposed to a liquid during passage through a medicament applicator,but regains a hydrogel structure and forms cohesive depots in the body.See Lee et al., J. Contr. Rel. 136: 88-98, 2009 which is incorporatedherein by reference. Semisolid formulations comprised of solid lipidnanoparticles loaded with pharmaceuticals and Carbopol® 934 poly(acrylicacid) microgel have thixotropic properties and may be used as topicalparticulate carriers for antifungal agents. See Lee et al., Ibid. Aparticulate thixotropic medium combined with naproxen and co-deliveredat high velocity to wrist joint tissues may achieve increasedpenetration of epidermal tissue, fibrous capsule, subsynovial tissue andsynovial membrane. Moreover, the properties of the thixotropic mediumwill lead to formation and deposition of a viscous liquid or hydrogelsolution containing naproxen onto wrist joint tissues and into the wristjoint synovial cavity.

The glove device may be worn throughout the day and activated as neededby the patient via an electronic switch that controls the piezoelectricactuators driving multiple microjets. For example an electronic switchon the glove device may be turned on voluntarily by the patient “asneeded” in response to pain and stiffness. Micro-circuitry, including atimer in the glove device may determine the duration of drug delivery(and therefore dose) following activation of the device. Alternatively,the glove device with micro-circuitry may be programmed to periodicallydeliver naproxen transdermally throughout the day and night on apredetermined dose and schedule as determined by the patient or thepatient's physician with no need for manual activation.

Example 5 A Patch Device with Embedded Microjets and Sensors to MonitorMovement and Piezoelectric Actuators Configured to Deliver Naproxen(e.g., Naprosyn®) to an Arthritic Finger Joints at High LocalConcentrations in a Time Dependent Manner

A device is provided to treat a patient with one or more arthriticfinger joints. The device is a patch that is worn on the affected jointsand delivers high local concentrations of an anti-inflammatory drug tothe one or more finger joints using microjets that are driven bypiezoelectric actuators. The device also contains sensors to monitor thegait of the patient and to signal the applicator to deliver ananti-inflammatory, naproxen. The patient who has chronic pain andstiffness in a one or more joints of the hand is clinically diagnosed tohave moderate osteoarthritis as confirmed by radiography. To reduce painand stiffness a patch device is placed in contact with the affectedjoints of the hand and positioned to substantially align multipleembedded microjets with one or more of the superior, inferior, lateral,medial, posterior or anterior aspects of the one or more finger jointsas well as sensors to monitor the patient's gait. The patch device alsohas sensors to monitor the arthritic patient's gait. A sensor to monitorgait is described by Miesel et al., U.S. 2007/0250134 A1 entitled“Collecting Gait Information for Evaluation and Control of Therapy”published Oct. 25, 2007 which is incorporated herein by reference. Themultiple embedded microjets are configured to provide transdermaldelivery of highly concentrated therapeutic medicaments localized to theone or more finger joints and may effectively deliver the therapeuticmedicaments to tissues of the one or more finger joints without risk ofadverse reactions associated with oral systemic medicament. The devicecan deliver highly concentrated therapeutic medicaments to tissues ofthe one or more finger joints including one or more of a fibrouscapsule, subsynovium, synovial membrane, synovium, joint cavity,synovial fluid, articular cartilage, subchondral bone, or ligament. Thepatch device may be held in place by velcro strips and alignment of themicrojets to the synovial joint is referenced to the location of the oneor more finger joints. Alternatively, the patch device may be held inplace with adhesive. The patch device with embedded microjets may bealigned to the affected finger joints by visual inspection. Themicrojets are connected to a reservoir containing naproxen (Naprosyn®,available from Roche Laboratories, Nutley, N.J.) to provideanti-inflammatory medicament for repeated local delivery to the one ormore finger joints. Local delivery of concentrated naproxen solutions(e.g., approximately 25-200 mg/ml) may be achieved while avoidingpotential adverse reactions. For example, a single microjet activatedwith a piezoelectric crystal may transdermally deliver approximately 28mg of a drug in a day from a reservoir with a 20 mg/ml solution of drug.See, e.g., Arora et al., Proc. Natl. Acad. Sci. USA, 104: 4255-4260,2007, which is incorporated herein by reference. Localized dosing of aconcentrated naproxen suspension (e.g., Naprosyn® suspension 25 mg/ml,available from Roche Laboratories, Nutley, N.J.) at the one or morefinger joints may be accomplished with a patch device containingmultiple embedded microjets actuated by piezoelectric actuators that arecontrolled electronically using a lithium battery as a source of power.Piezoelectric crystal actuators expand when electronically activated todrive small liquid volumes (e.g., 10-15 nanoliters) through a microjetat high velocity (greater than 100 meter/sec). The high velocity (ν>100m/s) of microjets allows their entry into the skin, whereas the smalljet diameters (50-100 μm) and extremely small volumes (2-15 nanoliters)limit the penetration depth (˜200 μm) See, e.g., U.S. 2008/0091139entitled “Methods, Devices and Kits for Microjet Drug Delivery”published Apr. 17, 2008; and Arora et al., Ibid. The rate of drugdelivery may be modulated by varying the electronic signal frequency.For example, electronic signals to piezoelectronic crystals at 10 Hzactuate microjets ten times faster than 1 Hz signals and increase therate of drug delivery by ten-fold. See, e.g., Arora et al., Ibid. Inaddition, the dosing of naproxen may also be controlled by variation ofthe drug concentration in the reservoir. Drug solutions or suspensionsmay be approximately 2 mg/ml, up to approximately 20 mg/ml, or up toapproximately 200 mg/ml.

A patch device may contain sensors to monitor the movements of the handsand fingers of the patient and to actuate the applicator. The sensorsmay transmit information to the patient, healthcare workers andcaregivers. For example, a wearable, hand-mounted movement monitor maybe comprised of a triaxial accelerometer and a microcontroller withmicro-circuitry and software as shown by Karantonis, et al., IEEE Trans.Info. Tech. Biomed. 10: 156-167, 2006 which is incorporated herein byreference. The triaxial accelerometer may be comprised of twoorthogonally mounted dual axis accelerometers, e.g., MXR7210GL,available from MEMSIC, Inc., North Andover, Mass. A microcontroller,e.g., MSP430F149 available from Texas Instruments, Dallas, Tex., samplesoutput signals from the accelerometers and the data are subject to aclassification algorithm embedded in flash memory of themicrocontroller. See Karantonis et al., Ibid. for details of themicrocontroller and the movement classification algorithm. A movementsensor may distinguish between periods of activity and rest, recognizepostural orientation, detect hand movement and provide an estimate ofmetabolic energy expenditure. The movement sensor and connectedmicrocontroller may also include predetermined parameters of posture,movement and metabolic energy expenditure that represent thresholds forsignaling to actuators, e.g., solenoids, of the applicator to delivernaproxen to the one or more finger joints of the patient. Parameters ofposture, movement and energy expenditure may be derived from historicaldata obtained with the movement sensor from the current patient or fromprevious patients. The movement sensor and microcontroller may transmitdata on movement, posture, and energy expenditure to the patient,healthcare workers, and caregivers as well as data on the dosing andscheduling of naproxen delivery.

The patch device with a medicament applicator and motion sensors has apower source and micro-circuitry to control the dose and schedule ofnaproxen delivered to the one or more finger joints. A lithium batterymay provide electric current to drive solenoid actuator valves and aminipump which are connected to a therapeutic medicament reservoir andmicroneedle arrays. Delivery of naproxen may be manually controlled byflipping a switch which provides electric current to the applicator.This may be done “as needed” for pain and stiffness. The dose ofnaproxen delivered may be determined by the concentration of naproxen inthe reservoir and the duration of the electric current. Micro-circuitrymay monitor the total dose of naproxen delivered within 24 hours andcontrol drug delivery to prevent exceeding the maximum recommended dose.The patch device may also have micro-circuitry including a timer thatallows the patient or a healthcare worker to program a dose and scheduleof naproxen delivery. The dosing schedule may span hours, days, weeks,or months. The micro-circuitry can record and store total dosage and/ordosage within a fixed time period of hours, days, weeks, or months. Thepatch device may transmit information including drug dosage, schedule,and drug consumption to a computer network system that is accessible bythe patient, the patient's family, healthcare providers, insurancecompanies, regulatory authorities and/or public health officials.

Example 6 A Desktop Device with a Medicament Applicator and Sensors toIdentify, Locate and Deliver Diclofenac Sodium (e.g., Voltaren®) toInflamed Joints of the Wrists and Hands of a Patient with RheumatoidArthritis

A device is provided to treat a patient with arthritic hands and wrists.The device is a desktop unit including an enclosure that surrounds oneor more hands and wrists and delivers high local concentrations ofmedicaments to the hands and wrists using microjets that are driven bypiezoelectric actuators. The patient who has symmetric polyarthritiswith swelling of the hand joints displays morning stiffness and testspositive for rheumatoid factor is clinically diagnosed to haverheumatoid arthritis. To reduce pain and stiffness in one or more jointtissues and to modify the disease process in a mammalian subject, adesktop device with sensors is used to detect inflamed joints and toalign multiple embedded microjets with the inflamed joints of the handand wrist. The patient's hand is inserted into the desktop device andthe hand is imaged within the desktop device, e.g., with ultrasound, tolocate the position of inflamed joints in the hand and wrist. Themultiple embedded microjets are aligned with the joint tissues of thehand, and the multiple embedded microjets are configured to providetransdermal delivery of highly concentrated therapeutic medicamentslocalized to the hand and wrist joints. The device including multipleembedded microjets aligned to the one or more joint tissues mayeffectively deliver the therapeutic medicaments to tissues of the handand wrist joints including one or more of a fibrous capsule,subsynovium, synovial membrane, synovium, joint cavity, synovial fluid,articular cartilage, subchondral bone, or ligament without risk ofadverse reactions that are associated with oral systemic medicaments fortreatment of joint disease.

A desktop device with openings for insertion of a right and left handcontains multiple microjets supported by glove-like templates inpositions corresponding approximately to the 14 joints present on eachhand and to the wrist joint. The device openings are designed withglove-like templates that immobilize a right hand and a left hand of thepatient in sizes ranging from small to large. For example, hands mayrange between approximately 154.51 mm-214.9 mm in length, and 71.62mm-119.06 mm in breadth. See Mandahawi et al., Int. J. Indust. Ergon.38: 966-976, 2008, which is incorporated herein by reference. Ultrasoundsensors present in the desktop unit detect the joints of the hands andwrist and transmit signals locating multiple microjets proximal to thejoints of the hand and wrist including one or more of theinterphalangial articulations, metacarpophalangeal joints, intercarpalarticulations and the radiocarpal joint. Positioning systems forultrasound can be used in the desktop device. See, e.g., U.S. 7128711entitled “Positioning systems and methods for guided ultrasound therapysystems” issued to Medan et al on Oct. 31, 2006, which is incorporatedby reference herein. Ultrasound sensors can be used that are suitablefor three dimensional medical imaging. See e.g., Huang et al., AppliedPhysics Letters 92: 193509, 2008, which is incorporated herein byreference. Ultrasound sound images are analyzed by computer software toidentify inflamed hand and wrist joints. Computer analyses may beconfirmed by a physician or an imaging expert. The desktop device andassociated computer system can target inflamed joints for treatment andcan actuate the corresponding microjets to deliver anti-inflammatory andanti-rheumatic medicaments to the one or more joint tissues of thepatient. Moreover the computer system records the dose and schedule ofmedicaments delivered to each joint of the hand and wrist, and theinformation is used along with the patient's medical history to planfuture treatment plans.

The microjets are connected to a reservoir containing diclofenac(Voltaren®, available from Novartis Pharmaceuticals Corp., East Hanover,N.J.) and methotrexate, e.g., Trexall® available from TevaPharmaceuticals USA, North Wales, Pa., to provide anti-inflammatorymedicament and a disease-modifying anti-rheumatic drug respectively forlocal delivery to the hand and wrist joints. Local delivery ofconcentrated diclofenac sodium solutions, e.g., approximately 25-200mg/ml, and concentrated methotrexate solutions, e.g., 75-250 mg/ml, maybe achieved while avoiding potential systemic adverse reactions and druginteractions. Local delivery of concentrated diclofenac sodium andmethotrexate solutions with microjets provides high doses of medicamentslocalized to one or more joint tissues without the likelihood of adverseevents and drug interactions that can be associated with systemic oralmedicaments. For example, a single microjet activated with apiezoelectric crystal may transdermally deliver approximately 28 mg of adrug in a day from a reservoir with a 20 mg/ml solution of drug. See,e.g., Arora et al., Proc. Natl. Acad. Sci. USA, 104: 4255-4260, 2007,which is incorporated herein by reference. Localized dosing of aconcentrated diclofenac (Voltaren®, available from NovartisPharmaceuticals Corp., East Hanover, N.J.) at hand and wrist joints maybe accomplished with a desktop device containing multiple embeddedmicrojets actuated by piezoelectric actuators that are controlledelectronically using a lithium battery as a source of power.Piezoelectric crystal actuators expand when electronically activated todrive small liquid volumes, e.g., 10-15 nanoliters, through a microjetat high velocity, greater than 100 meter/sec. See, e.g., U.S.20080091139 entitled, “Methods, Devices and Kits for Microjet DrugDelivery” published Apr. 17, 2008; and Arora et al., Ibid. The rate ofdrug delivery may be modulated by varying the electronic signalfrequency. For example, electronic signals to piezoelectronic crystalsat 10 Hz actuate microjets ten times faster than 1 Hz signals andincrease the rate of drug delivery by ten-fold. See, e.g., Arora et al.,Ibid. In addition, the dosing of diclofenac sodium may also becontrolled by variation of the drug concentration in the reservoir. Drugsolutions or suspensions may be approximately 2 mg/ml, up toapproximately 20 mg/ml, or up to approximately 200 mg/ml.

Each recited range includes all combinations and sub-combinations ofranges, as well as specific numerals contained therein.

All publications and patent applications cited in this specification areherein incorporated by reference to the extent not inconsistent with thedescription herein and for all purposes as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference for all purposes.

Those having ordinary skill in the art will recognize that the state ofthe art has progressed to the point where there is little distinctionleft between hardware and software implementations of aspects ofsystems; the use of hardware or software is generally (but not always,in that in certain contexts the choice between hardware and software canbecome significant) a design choice representing cost vs. efficiencytradeoffs. Those having ordinary skill in the art will appreciate thatthere are various vehicles by which processes and/or systems and/orother technologies described herein can be effected (e.g., hardware,software, and/or firmware), and that the preferred vehicle will varywith the context in which the processes and/or systems and/or othertechnologies are deployed. For example, if an surgeon determines thatspeed and accuracy are paramount, the surgeon may opt for a mainlyhardware and/or firmware vehicle; alternatively, if flexibility isparamount, the surgeon may opt for a mainly software implementation; or,yet again alternatively, the surgeon may opt for some combination ofhardware, software, and/or firmware. Hence, there are several possiblevehicles by which the processes and/or devices and/or other technologiesdescribed herein can be effected, none of which is inherently superiorto the other in that any vehicle to be utilized is a choice dependentupon the context in which the vehicle will be deployed and the specificconcerns (e.g., speed, flexibility, or predictability) of the surgeon,any of which may vary. Those skilled in the art will recognize thatoptical aspects of implementations will typically employoptically-oriented hardware, software, and or firmware.

In a general sense, the various aspects described herein can beimplemented, individually and/or collectively, by a wide range ofhardware, software, firmware, or any combination thereof can be viewedas being composed of various types of “electrical circuitry.”Consequently, as used herein “electrical circuitry” includes, but is notlimited to, electrical circuitry having at least one discrete electricalcircuit, electrical circuitry having at least one integrated circuit,electrical circuitry having at least one application specific integratedcircuit, electrical circuitry forming a general purpose computing deviceconfigured by a computer program (e.g., a general purpose computerconfigured by a computer program which at least partially carries outprocesses and/or devices described herein, or a microprocessorconfigured by a computer program which at least partially carries outprocesses and/or devices described herein), electrical circuitry forminga memory device (e.g., forms of random access memory), and/or electricalcircuitry forming a communications device (e.g., a modem, communicationsswitch, or optical-electrical equipment). The subject matter describedherein can be implemented in an analog or digital fashion or somecombination thereof.

The herein described components (e.g., steps), devices, and objects andthe description accompanying them are used as examples for the sake ofconceptual clarity and that various configuration modifications usingthe disclosure provided herein are within the skill of those in the art.Consequently, as used herein, the specific examples set forth and theaccompanying description are intended to be representative of their moregeneral classes. In general, use of any specific example herein is alsointended to be representative of its class, and the non-inclusion ofsuch specific components (e.g., steps), devices, and objects hereinshould not be taken as indicating that limitation is desired.

With respect to the use of substantially any plural or singular termsherein, those having skill in the art can translate from the plural tothe singular or from the singular to the plural as is appropriate to thecontext or application. The various singular/plural permutations are notexpressly set forth herein for sake of clarity.

The herein described subject matter sometimes illustrates differentcomponents contained within, or connected with, different othercomponents. It is to be understood that such depicted architectures aremerely exemplary, and that in fact many other architectures can beimplemented which achieve the same functionality. In a conceptual sense,any arrangement of components to achieve the same functionality iseffectively “associated” such that the desired functionality isachieved. Hence, any two components herein combined to achieve aparticular functionality can be seen as “associated with” each othersuch that the desired functionality is achieved, irrespective ofarchitectures or intermedial components. Likewise, any two components soassociated can also be viewed as being “operably connected,” or“operably coupled,” to each other to achieve the desired functionality,and any two components capable of being so associated can also be viewedas being “operably couplable,” to each other to achieve the desiredfunctionality. Specific examples of operably couplable include but arenot limited to physically mateable or physically interacting componentsor wirelessly interactable or wirelessly interacting components orlogically interacting or logically interactable components.

While particular aspects of the present subject matter described hereinhave been shown and described, it will be apparent that, based upon theteachings herein, changes and modifications may be made withoutdeparting from the subject matter described herein and its broaderaspects and, therefore, the appended claims are to encompass withintheir scope all such changes and modifications as are within the truespirit and scope of the subject matter described herein. Furthermore, itis to be understood that the invention is defined by the appendedclaims. It will be understood that, in general, terms used herein, andespecially in the appended claims (e.g., bodies of the appended claims)are generally intended as “open” terms (e.g., the term “including”should be interpreted as “including but not limited to,” the term“having” should be interpreted as “having at least,” the term “includes”should be interpreted as “includes but is not limited to,” etc.). Itwill be further understood that if a specific number of an introducedclaim recitation is intended, such an intent will be explicitly recitedin the claim, and in the absence of such recitation no such intent ispresent. For example, as an aid to understanding, the following appendedclaims may contain usage of the introductory phrases “at least one” and“one or more” to introduce claim recitations. However, the use of suchphrases should not be construed to imply that the introduction of aclaim recitation by the indefinite articles “a” or “an” limits anyparticular claim containing such introduced claim recitation toinventions containing only one such recitation, even when the same claimincludes the introductory phrases “one or more” or “at least one” andindefinite articles such as “a” or “an”; the same holds true for the useof definite articles used to introduce claim recitations. In addition,even if a specific number of an introduced claim recitation isexplicitly recited, such recitation should typically be interpreted tomean at least the recited number (e.g., the bare recitation of “tworecitations,” without other modifiers, typically means at least tworecitations, or two or more recitations). Furthermore, in thoseinstances where a convention analogous to “at least one of A, B, and C,etc.” is used, in general such a construction is intended in the senseof the convention (e.g., “a system having at least one of A, B, and C”would include but not be limited to systems that have A alone, B alone,C alone, A and B together, A and C together, B and C together, or A, B,and C together, etc.). In those instances where a convention analogousto “at least one of A, B, or C, etc.” is used, in general such aconstruction is intended in the sense of the convention (e.g., “a systemhaving at least one of A, B, or C” would include but not be limited tosystems that have A alone, B alone, C alone, A and B together, A and Ctogether, B and C together, or A, B, and C together, etc.). Virtuallyany disjunctive word and/or phrase presenting two or more alternativeterms, whether in the description, claims, or drawings, should beunderstood to contemplate the possibilities of including one of theterms, either of the terms, or both terms. For example, the phrase “A orB” will be understood to include the possibilities of “A” or “B” or “Aand B.”

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopeand spirit being indicated by the following claims.

1.-47. (canceled)
 48. A method comprising: injecting one or moremedicaments to one or more joint tissues of a mammalian subject, whereinthe injecting of the one or more medicaments is via a device includingone or more sheaths configured to contact one or more body contours inproximity to one or more joints of articulating bone of the mammaliansubject; and one or more microjet applicators supported by the one ormore sheaths and configured to inject one or more medicaments to one ormore joint tissues of the mammalian subject.
 49. The method of claim 48,wherein the one or more applicators include one or more high speedmicrojets.
 50. The method of claim 49, wherein the high speed microjetsare nanoliter-volume pulsed microjets.
 51. The method of claim 48,wherein the one or more sheaths includes a sleeve-shaped article ofclothing or a sleeve-shaped body covering.
 52. The method of claim 51,wherein the one or more sheaths includes shirt sleeve, pant, legcovering, glove, stocking, bandage-like covering, brace, knee brace,elbow brace, ankle brace, foot brace, hand brace, or spinal brace. 53.The method of claim 48, wherein the one or more joint tissues includesone or more of a fibrous capsule, subsynovium, synovial membrane,synovium, joint cavity, synovial fluid, articular cartilage, subchondralbone, or ligament.
 54. The method of claim 48, wherein the one or morejoints includes a synovial joint, cartilaginous joint, or fibrous joint.55. The method of claim 48, wherein the one or more applicatorssupported by the one or more sheaths are configured to respond to one ormore sensors, wherein the one or more applicators are configured toinject the one or more medicaments to the one or more joint tissues ofthe mammalian subject.
 56. The method of claim 48, further includingproviding one or more sensors configured to detect movement of the oneor more body contours.
 57. The method of claim 56, wherein the one ormore sensors are configured to monitor joint movement, body movement, orgait of the mammalian subject.
 58. The method of claim 56, wherein theone or more sensors are configured to monitor posture of the mammaliansubject.
 59. The method of claim 48, further including providing one ormore sensors configured to detect one or more physiological conditionsof the mammalian subject.
 60. The method of claim 59, wherein the one ormore sensors are configured to detect tissue swelling, tissue pressure,tissue color, tissue temperature, environmental temperature, electricalproperty of tissue, optical property of tissue, perspiration, orpresence of an analyte.
 61. The method of claim 60, wherein the analyteincludes an inflammatory marker, antibody, or cytokine.
 62. The methodof claim 48, further including providing one or more sensors configuredto determine quality of location or quality of contact placement of theone or more sheaths on the one or more body contours.
 63. The method ofclaim 48, further including providing a controller configured to controlrelease of the one or more medicaments from the one or more applicators.64. The method of claim 63, wherein the controller is configured tocontrol a timed-release dosage of the one or more medicaments.
 65. Themethod of claim 63, wherein the controller is configured to reportquantity and frequency of dosage of the one or more medicaments.
 66. Themethod of claim 63, wherein the controller is configured to control amaximum dosage of the one or more medicaments for a time period.
 67. Themethod of claim 63, further including providing one or more sensors,wherein the controller is configured to respond to the one or moresensors.
 68. The method of claim 67, wherein the one or more sensors areconfigured to detect one or more conditions at one or more of the one ormore joints and the controller is configured to control release of theone or more medicaments at others of the one or more joints of themammalian subject.
 69. The method of claim 68, wherein the one or moresensors are configured to detect one or more physiological conditions ofthe mammalian subject.
 70. The method of claim 68, wherein the one ormore sensors are configured to detect movement of the one or more bodycontours.
 71. The method of claim 48, wherein the one or moreapplicators further include tissue permeabilization components includingone or more of electronics, ultrasonics, chemical permeation enhancer,iontophoresis, microdialysis, ultrafiltration, electromagnetic,electroosmosis, sonophoresis, microdialysis, suction, electroporation,thermal poration, microporation, heating component, or laser.
 72. Themethod of claim 48, wherein the one or more sheaths includes atourniquet configured to apply intermittent pressure in the region ofthe jointed area.
 73. The method of claim 72, wherein the tourniquet isconfigured to apply a constricting force thereby causing the one or moreapplicators to penetrate the stratum corneum of the skin of themammalian subject.
 74. The method of claim 49, further includingproviding a component for transient mechanical/electrical accelerationof the one or more medicaments from the high speed microjets.
 75. Themethod of claim 74, wherein the component for transientmechanical/electrical acceleration includes a fluid displacementactuator configured as one or more piezoelectric actuators, one or moresprings, one or more solenoids, one or more magnets, one or more motors,or one or more compressed gas actuators.
 76. The method of claim 74,wherein the component for mechanical/electrical acceleration appliesconcentration gradients of the one or more medicaments in atime-dependent manner.
 77. The method of claim 48, wherein the one ormore medicaments includes steroids, corticosteroids, analgesics, COX-2inhibitors, or NSAID.
 78. The method of claim 48, further includingproviding a pharmaceutical composition including the one or moremedicaments in a thixotropic medium.
 79. The method of claim 48, whereinthe one or more applicators are configured to apply the one or moremedicaments in a time-dependent manner.
 80. The method of claim 79,wherein the one or more applicators are configured to apply the one ormore medicaments in concentration gradients in the time-dependentmanner.
 81. The method of claim 79, wherein the one or more medicamentsis configured to have a short effective half-life.
 82. The method ofclaim 79, wherein the one or more medicaments is configured to have along effective half-life. 83.-132. (canceled)